Identification of tissue/cell specific marker genes and use thereof

ABSTRACT

A cartilage array comprises a plurality of different polynucleotide probe spots stably associated with a solid surface of a carrier, whereby each of said spots is made of a unique polynucleotide that corresponds to one specific cartilage marker gene. Said specific cartilage marker genes preferably are at least in part selected from a group of 467 genes that could be shown to be cartilage related.

CROSS REFERENCES TO RELATED APPLICATIONS

This application claims the priority of U.S. provisional patent application 60/388,994, filed Jun. 14, 2002, the disclosure of which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

The present invention relates to a method for the identification of tissue cell specific marker genes, a method for the determination of a disease state or developmental status of cells/tissue as well as to gene expression profiling of cartilage tissue. More specifically, the invention relates to microarrays containing a plurality of selected human chondrocyte specific sequences and their use for classification of cartilage donor tissue or generation of characteristic gene expression profiles of in vitro chondrocyte cultures. Such DNA arrays find use as a standard tool of molecular biology research and clinical diagnostics for all cartilaginous or related tissues.

BACKGROUND OF THE INVENTION

Limitation on Current Microarray Technologies

DNA array technology, also known as biochip or microarray technology, is currently revolutionizing modern biology. In this technology, a biological sample is applied to a glass slide or chip covered with an array of immobilized DNA probes. Sample nucleic acid complementary to specific probes on the array hybridizes and can be detected with high sensitively with automated, computerized detectors. In this manner, hundreds to thousands of different individual hybridization experiments can be performed simultaneously. This allows assays of enormous complexity to be carried out—for example, an analysis of the entire gene expression profile of a cancer cell—with simplicity unimaginable only a few years ago. As a consequence many patents as well as scientific publications have accumulated during the last years. U.S. Pat. No. 6,194,158 discloses characteristic genes and gene expression useful in screening for, diagnosis of, monitoring of, and therapeutic treatment of brain cancer. U.S. Pat. No. 6,218,122 discloses methods for determining or monitoring the progression of disease states or the efficacy of therapeutic regimens within human patients. U.S. Pat. No. 6,077,673 discloses mouse arrays having a plurality of probe polynucleotides corresponding to a key mouse gene for expression analysis of critical mouse genes. A list of representative scientific papers dealing with monitoring the expression level of a large number of transcripts within a cell at any time are as follows: Schena et al., 1995, Quantitative monitoring of gene expression patterns with a complementary DNA-microarray, Science 270: 467-470; Lockhart et al., 1996, Expression monitoring by hybridization to high-density oligonucleotide arrays, Nature Biotechnology 14:1675-1680; Blanchard et al., 1996, Sequence to array: Probing the genome's secrets, Nature Biotechnology 14:1649. Qi et al., 2003, Identification of genes responsible for osteoblast differentiation from human mesodermal progenitor cells PNAS 18; 100 (6):3305-10. While this list of scientific papers and patents reflects without any doubt the great potential of microarrays, there are a couple of yet unsolved problems that are more and more discussed among the scientific community. Especially, these problems are data overflow, representative sample collection, RNA processing and inappropriate data analysis. It is even suspected that within next five years, many of conclusions drawn from published data will be revised or refuted. Thus there remains a real and unmet need for advanced microarray solutions, targeted to specific tissues above all with respect to simplification and substantiation of the process of data generation and data handling. With respect to this issue the disclosed invention has made considerable contribution in the cartilage area with a cartilage-specific microarray containing a manageable number of cartilage relevant genes.

Limitation on the Number of Cartilage Relevant Genes

Until today the number of cartilage-relevant genes (genes that have been associated a potential functional role on cartilage biology, homeostasis or pathology) is very limited. Approximately, 100-200 genes have been described in the literature in any relationship to cartilage tissue. While existing publications e.g. Heller et al PNAS, 94; 2150-2155; 1997 have described analysis of inflammatory diseases of cartilage and Sekiya et al PNAS 99; 43974402; 2001 cartilage formation from stem cells with microarrays, a comprehensive analysis and determination of characteristic gene expression profiles for 2D, 3D, fetal, adult and pathological chondrocytes cell cultures cultivated under different conditions has not been performed up to now. While in patent WO01/24833 A2 a few markers have been determined that are associated with chondorcytes and their phenotype stability, it will not be possible to perform a detailed gene expression analysis and to define specific fingerprints. Therefore the possibility of characterizing culture conditions or cartilage tissue samples can not be thoroughly addressed.

Completion of the human genome first project draft on 2000 has revealed that the human genome comprises ˜30000-35000 human genes. Estimates show that the number and type of active genes vary significantly between different tissues and may increase up to a couple of 10000 for complex tissues, e.g. brain. As a consequence, many genes albeit fully sequenced may have yet not been, disclosed to be functionally up- or down regulated in cartilage or cartilage derived cells. The inventive approach described herein has made possible to up to now disclose a total of 467 known and additional genes being differentially expressed in a significant and objective manner within chondrocytes or chondrogenic cells.

By means of the already known and additionally found to be cartilage related genes, a strategy to best address and represent chondrocytes cultured under different conditions has been developed in the scope of the present invention.

SUMMARY OF THE INVENTION

In a first aspect the present invention relates to a method for the identification of tissue/cell specific marker genes comprising

-   -   a) taking tissue and/or cells of at least one developmental         stage and/or at least one disease state, and/or     -   cultivating said tissue and/or cells in vitro under at least one         culture condition,     -   b) determination of gene expression profiles of said         tissue/cells and/or in vitro cultivated tissue/cells and     -   c) identification of specific marker genes by bioinformatic         analysis of said gene expression profiles.

In particular, the first aspect relates to a method for the identification of tissue/cell specific marker genes comprising cultivating tissue/cells of different developmental stages and/or health conditions in vitro under different culture conditions, determination of gene expression profiles of said in vitro cultivated cartilage tissue and identification of specific marker genes by bioinformatic analysis of said gene expression profiles.

In a preferred embodiment said tissue is selected from the group consisting of fetal tissue, adolescent tissue, adult tissue, healthy tissue, pathological tissue, progenitor cells such as stem cells or cells derived from the same precursor lineage. Preferred culture conditions are 2D and 3D in vitro cultures and the gene expression profiles are preferably determined by means of a micro-array. The bioinformatic analysis of said gene expression profiles is preferably done by cluster software such as e.g cluster analysis.

In a preferred embodiment said tissue is cartilage.

A second aspect of the present invention relates to a method for the determination of a disease state or developmental status of cells/tissue or the physiological potential of cells/tissue. Said method comprises establishing a profile of cellular constituents, preferably a gene expression profile, of said cells or tissue, comparison of said resulting gene expression profile with gene expression profiles characteristic for a particular status or physiological potential of the examined cells or tissue.

Said method can e.g be used to assess the redifferentiation potential of cells or tissue, the assessment of the quality of tissue biopsies for diagnostic and prognostic purposes regarding in vitro tissue engineering applications, the assessment of the quality of in vitro produced cells such as e.g. mesenchymal cells, stem cells or embryonic cells or of in vitro produced tissue for therapeutical applications and for determining the effect of one or more growth factors, media compositions or drugs on cells or tissue. Based on said method it is e.g. possible to set up different in vitro culture conditions for cells/tissue allowing the cultivation of cells/tissue which retain their potential for differentiation.

In a preferred embodiment said cells or tissue is cartilage tissue or chondrocytes and the array comprises polynucleotide probes of tissue specific marker genes.

In a further preferred embodiment said profile is a gene expression profile which is determined by means of a micro-array.

A further object of the present invention is a method for the determination of characteristic profits for clinical use comprising correlating the patient data of the biopsy donor with the gene expression profile of said biopsy cells/tissue. Preferably said gene expression profile has been determined according to the above disclosed method. The resulting profiles of said method are suitable tools in the clinic allowing an evaluation of further treatments of a patient.

The present invention provides characteristic gene expression profiles experimentally determined by using cartilaginous tissues as from individual human donors of various ages (fetal, adolescent, adult) and health conditions (healthy and arthritic) or cells thereof cultivated under different in vitro culture conditions (2D and 3D in vitro cultures, time follow ups). From these different gene expression profiles a set of hitherto 467 markers has been deduced that can be used to design and produce a cartilage specific microarray for commercial applications in the field of R&D, such as culture media development, drug screening etc., but also for clinical applications.

Gene expression analysis performed with such microarrays and the corresponding analytical procedure thereof can be used to assess quality control of human donor cartilage, e.g. biopsy and therefore optimization of any downstream tissue engineering process, for diagnostic evaluation of the patient and its candidate treatment methods, to ensure a cost-optimized procedure, to investigate and assess all kind of 2D- and 3D in vitro cultures performed with human chondrocytes or chondrogenic cells, e.g. stem cells, to screen all kind of drugs, e.g. hormones, growth factors within the above mentioned in vitro cultures regarding a potential beneficial effect and quality assessment of in vitro produced tissue performed by tissue engineered procedures.

In a further aspect the present invention provides a cartilage array comprising a plurality of different polynucleotide probe spots stably associated with a solid surface of a carrier, whereby each of said spots is made of a unique polynucleotide that corresponds to one specific cartilage marker gene.

A preferred cartilage array of the present invention comprises at least two spots that have different nucleotide sequences but of the same cartilage marker gene, more preferably at least 10 spots indicative for one tissue or cell status, whereby said at least 10 spots can be selected from different sequences of one gene or from different genes or a combination thereof.

In a preferred embodiment said polynucleotides of the array do not cross hybridize under stringent conditions with each other.

In a preferred embodiment of the present invention the cartilage array comprises spots that are indicative for at least two tissue or cell status, preferably 3.

A further preferred inventive cartilage array is an array wherein at least part of the cartilage marker genes are selected from the 467 genes listed in the description, preferably at least 10%, more preferably at least 50%, most preferably about 100%.

A further preferred inventive cartilage array is an array wherein at least part of the cartilage marker genes are selected from a subgroup of the 467 genes listed in the description, wherein said subgroup consists of the most tissue specific 200 genes.

In another preferred embodiment the status is selected from biopsies and/or 2D cultures and/or 3D cultures of healthy adult, healthy fetal/infant, undesired adult, undesired fetal/infant or progenitor cells like e.g. stem cells or cells derived from the same precursor lineage.

In a further preferred embodiment of the present invention the polynucleotide probes of the cartilage array have a length of at least 10 nucleotides, preferably at least 20 nucleotides. The probes can also have a length of 30 nucleotides, 50 nucleotides or 70 nucleotides. It is as well possible to use PCR derived products produced from cDNA clones.

In a preferred embodiment the carrier of the inventive cartilage array is attached to coated glass, nylon or any other material.

A further object of the present invention is a kit for use in a hybridization assay, wherein said kit comprises a cartilage array of the present invention. In a preferred embodiment said kit comprises reagents for generating a labelled target polynucleotide sample, a hybridization buffer and a wash medium.

DESCRIPTION OF THE FIGURES

The present invention will be further understood from the following description with reference to the tables and figures where:

Tab. I shows the determined number of all genes in the corresponding SOM analysis being differentially expressed according to microarray analyses of a variety of in vitro chondrocyte cultures according to predefined criteria. From these data sets specific expression profiles can be deduced that are characteristic for different cell culture conditions.

Tab. II shows the extracted and reviewed genes deduced from Tab I in order to have only single entry numbers. Since most of these genes have never been described in any relationship to cartilage, they can be considered as novel cartilage marker (positive/negative markers) or key cartilage genes.

Tab III shows a subset of marker genes form Tab. II that has been used for the production of a micro-array. Included is a subset from Tab II and genes known from the literature.

Tab IV shows the results of the analysis of the 467 cartilage specific marker genes.

Tab V shows the samples used in Examples 1, 2 and 3. Human chondrocytes isolated from 4 different donors were proliferated and kept in 3D-like pellet culture for 7 and 14 days resulting in a total number of 12 samples.

FIG. 1 shows a classical result from an analysis performed with self-organizing-maps. This software clusters all genes together in sub clusters that show a similar expression profile. The number of marker genes for the corresponding analysis e.g. 2D vs. 3D cultures (see also Tab I) corresponds to the total number of genes in the sub clusters.

FIG. 2 shows an example of a graphical presentation of a cluster analysis and viewed by the software treeview. This shows how cells from different origin and potential for in vitro cartilage formation are related to each other and allow a clearer classification of the cell sources. Fetal cells clearly produce different gene clusters compared to adult chondrocytes, while failures are characterized by other gene clusters. Furthermore 3D cell cultures analyzed in a time dependent manner from different donors can be distinguished among each other and gene expression profiles will be grouped accordingly.

FIG. 3: SOM analysis of all culture conditions and samples described in Example 2 and in Tab V.

FIG. 4: SOM analysis for proliferated chondrocytes (t0) only, for the 4 donors. Gene expression pattern corresponding to donor 2 (the second spot from left hand side in every cluster) behaves different in most clusters.

FIG. 5: SOM analysis of chondrocytes kept in 3D culture condition for 7 days (t7). Gene expression pattern from donor 3 (the third spot from left hand side in every cluster) is different for example in clusters c2 and c5.

FIG. 6 shows self organized maps (SOM) of chondrocytes from same patients of FIGS. 4 and 5 kept under 3D culture condition for 14 days (t14).

FIG. 7: cluster analysis of all culture conditions and samples described in Example 2 and in Tab V. This figure shows a subset of 88 hierarchical clustered genes (rows) and samples (columns) demonstrating similar gene expression behavior of chondrocytes under different culture conditions. For example proliferated cells (#1, #2, #4, #5, #7, #8, #10, #11) can easily be discriminated from cells kept in 3D-like pellet culture for 14 days (3#, 6#, 9#, 12#).

FIG. 8: cluster analysis of human aortic fibroblasts vs. chondrocytes. This figure shows a subset of selected clusters of human aortic fibroblasts cells compared to human chondrocytes both kept in 3D pellet cultures for 14 days. The dendrogram in the upper part of the figure shows the ability of CART-CHIP™ 300 microarray described in this invention to discriminate between different cell lines.

FIG. 9: cluster analysis of Interleukin-1 treated vs. untreated human chondrocytes. This figure demonstrates a subset of representative gene clusters allowing differentiation between cells treated with Interleukin-1 from untreated cells both kept in 3D pellet cultures as well as for proliferated cells.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

2D cultures as used in the scope of the present invention are anchorage dependent chondrocyte cultures cultivated on plastic culture devices.

3D cultures as used in the scope of the present invention are chondrocytes cultured in a three dimensional environment, namely either a) scaffold-free, such as small high density pellet cultures (0.25-3.0*10⁶ cells) or as high density cultures using 50*10⁶ cells/ml or aliquots thereof; or b) by using a synthetic scaffold such as PGA, PLA, or mixtures thereof or biological substances such as agarose, alginate, chitosan or collagen.

failures as used in the scope of the present invention are chondrocytes cultured in a three dimensional environment that are not able to synthesize new extracellular matrix thereby compromising the production of new living tissue engineered cartilage equivalents.

gene expression profile as used in the scope of the present invention is a profile of genes that are up or down regulated according to different cell conditions.

fingerprint as used in the scope of the present invention refers to a gene expression profile characteristic for a cellular status.

tissue or cell status as used in the scope of the present invention refers to a tissue or cells therof having a certain metabolic or activity status.

new extracellular matrix as used in the scope of the present invention designates living cartilage-like tissue.

micro-array as used in the scope of the present invention is used in its original scope that encompasses embodiments today sometimes refused to as “macro-arrays”.

The Invention

The present invention provides cartilage-specific gene arrays as well as methods for their use. In the subject cartilage arrays, a plurality of polynucleotide probe spots are stably associated with the surface of a solid carrier, preferably a surface of a microscope glass slide. Each different polynucleotide probe spot is made of a unique polynucleotide that corresponds to a key cartilage gene of interest. Thus, the subject arrays find particular use in gene expression assays of key cartilage genes. In further describing the subject of the invention, the cartilage specific microarrays are first discussed, followed by a review of representative applications in which the subject arrays may be employed.

Arrays of the Subject Invention-General Description

Selection of Novel Key Cartilage Specific Genes:

A critical feature of the subject arrays is that all of the probe polynucleotide spots of the array correspond to human key cartilage genes that have been found through unique selection processes and criteria. As a result of said processes, up to now 467 different key human cartilage genes that are under tight transcriptional role have been discovered, some of them being not described before in any relationship to cartilage. In more detail, different microarray analyses were performed by using cartilaginous tissues as from individual human donors of various ages (fetal, adolescent, adult) and health conditions (healthy and arthritic) or cells thereof cultivated under different in vitro culture conditions (2D and 3D in vitro cultures, time follow ups). This variety of cartilage cell sources and different culture conditions was set up to grasp the highest possible number of genes differentially expressed and thus being indicative of a potential role.

It has been found that specific chondrocyte culture conditions are of great importance for the present invention that discloses a plurality of novel key cartilage genes as well as characteristic and meaningful gene expression patterns. For this reason, the strategy and criteria of the analysed in vitro human chondrocyte cultures are described in more detail. The principal experimental setup included both the cultivation of chondrocytes in an anchorage dependent condition, known as 2D cultures for expansion of cells e.g. where the passages is variable but at least more then one, as well as cultivation of chondrocytes in an anchorage independent condition, known as 3D cultures for (re-)differentiation and de novo tissue formation of cells. These are the key steps of any tissue engineering process where autologous tissue equivalents are produced. Since the cell source is either a small biopsy, a small bone marrow aspirate in case of mesenchymal stem cells or other tissue with a limited number of pre-chondrogenic cells, it is first necessary to isolate those cells in order to be able to multiply the cell number drastically. In case of a cartilage biopsy, cells are released from their surrounding extracellular matrix by collagenase digestion and then seeded onto the surface of plastic tissue culture flasks. The proliferation may take place either in the presence or absence of fetal serum combined with conventional DMEM/F12 medium. Cells can then be passaged by trypsin treatment over several rounds. As a major drawback of this necessary cell expansion, the cells loose their differentiated phenotype and assume a de-differentiated phenotype with altered gene expression. It is further known that with increasing number of passages the state of de-differentiation also advances. As a consequence, genes being transcriptionally upregulated under such artificial culture conditions are cartilage relevant in a manner being indicative of an undesired cellular status. It is also quite common to designate these genes as de-differentiation or negative markers. While healthy tissue in general has been found to re-differentiate in 3D culture after up to 4 passages in 2D cultures, tissue of undesired cellular status cultivated under usual conditions, such as usual culture media, usually does not re-differentiate in 3D culture after at most 4 passages in 2D culture.

Subculture modulated chondrocytes that do not express differentiation markers reexpress the differentiated phenotype in response to the anchorage—independence resulting from various 3D culture models, e.g. high density cultures, agarose or alginate cultures, or cultures within synthetic scaffolds such as made of polyglycolic acid (PGA), polylactic acid (PLA) or mixtures thereof. To set up three dimensional cell cultures the cells are detached after proliferation by trypsin treatment and embedded either in gel-like substances such as alginate, seeded within a porous scaffold such as PGA or cultivated as high-density cultures, only. The time for the analysis may vary and ideally addresses several time points (up to several weeks). Thus 3D in vitro chondrocyte cultures support the differentiated phenotype of chondrocytes and can be used to discover cartilage relevant genes or differentiation markers. It should be noted however, that reversibility of the de-differentiation process is dependent on the number of passages and can become irreversible or at least partially irreversible at higher passage numbers (under usual conditions at most about 4 passages). As a rule the time course of de- and re-differentiation are similar. During skeletal development, cartilage serves as a template for bone formation. Chondrocytes of fetal or infant (<1 year) or growth plate cartilage pass through different stages and exhibit several distinct phenotypes, such as resting, proliferating, and hypertrophic chondrocytes. Progression through each of these phases is accompanied by profound changes in gene expression patterns. Further, evidence has accumulated that the successful sequence of cartilage repair via tissue engineering recapitulates aspects of embryonic tissue formation. For these reasons, it is important to consider fetal and infant cartilaginous tissue. Cells isolated from human fetal/infant cartilage that are cultivated in 2D and 3D culture systems as described above are especially helpful to understand the mechanisms underlying the phenotypic instability of chondrocytes and the related gene expression patterns. These 2D and 3D culture system may then be analyzed to deduce gene expression profiles and to define marker genes that are characteristic for the (re-)differentiation process. Thus maintenance of chondrocyte-specific phenotype being crucial for normal structure and biomechanical properties of articular cartilage may be better understood and have important implications for modern therapeutic biological applications.

The above mentioned experimental setup for 2D and 3D cultures may be even expanded to compare human adult cells with human fetal/infant chondrocytic cells of age <1 year. The comparison of gene expression profiles of adult versus fetal/infant human chondrocytes during the in vitro cartilage formation process is an important aspect since marker genes associated with developmental aspects are revealed. This can be of further interest when 3D cell cultures need to be optimized for their in vitro performance for the production of new tissue by e.g. adding growth factors that are found to play a major role during the early onset of cartilage formation in vivo.

Another experimental setup found in the scope of this invention includes the in vitro culture of cells harvested from cartilaginous areas of arthritic knee joints. Osteoarthritis (OA) results from the failure of chondrocytes within the joint to maintain the balance between synthesis and degradation of extracellular matrix. OA is a multifactorial disorder in which aging, genetic, hormonal and mechanical factors are all major contributors to its onset and progression. With progressing disease state, the articular chondrocytes ability to maintain homeostasis and functionality is increasingly disappearing. As a consequence, the phenotype of osteoarthritic chondrocytes compared with normal chondrocytes exhibits remarkable changes. Gene expression profiling allows characterization of the osteoarthritic cellular phenotype, a key determinant for understanding and manipulation of osteoarthritic processes. By studying and comparing the gene expression profiles of chondrocytes harvested from pathological and healthy human cartilage areas it becomes possible to identify marker genes that are able to predict the future outcome of cell cultures used for in vitro tissue engineering applications. This also relates to the very critical question of the assessment of the quality of the starting biopsy material that is being used for downstream applications like tissue engineering. By having this important information before performing any downstream applications like e.g. proliferation and consecutive 3D in vitro tissue formation, the further steps of any process can then be adapted or even not performed at all because of inadequate quality of biopsy material. Such decision may be of high relevance when tissue-engineering processes are transferred or applied in the clinic. Gene expression profiling of chondrocytes may then be used as a diagnostic tool to allow and to choose that therapeutic approach with the most promising clinical outcome.

A further important aspect of the invention is the observation that chondrocytes derived from osteoarthritic patient material always qualify for anchorage dependent proliferation in 2D over several passages. These cells however, if subsequently induced to re-differentiate by culturing them as 3D high density pellets, do not survive over an extended time period, in most cases they die in culture by undergoing apoptosis. It is assumed that these cells, due to an altered phenotype, are not capable of producing the critical survival factors in the appropriate concentrations, above all extracellular matrix components providing intercellular spaces as they occur in native cartilage. Cells that are not suitable to be cultured within 3D high density cultures are herein referred to as “failures”. These impaired cell cultures can be used to set up representative “failure” systems, where cells from different pathological cartilage sources are harvested, proliferated and cultivated in 3D high density pellet culture systems. After each of these experimental steps, RNA can be isolated from the different cell sources and combined to create “failure pools”. These failure pools are very well suitable to identify general marker genes being indicative of the onset of osteoarthritis.

For finding cartilage relevant genes, and for determining their presence dependent on the specific cartilage type such as age, health etc., sufficient material must be generated, e.g. by 2D culturing over several passages, and optionally 3D culturing. Said material then can on be subjected to usual gene analyses, and the tissue specific genes determined. Cartillage samples are classified prior to culturing and/or after culturing to get the information needed for later interpretation of the gene expression profile.

A further experimental setup of the current inventions discloses the analysis of chondrocytes grown in 3D cultures isolated from pathological human cartilage and analyzed in a time dependent manner. This experimental set-up allows to study the apoptotic process and to further define additional dynamic and characteristic gene expression profiles, useful for deducing and further assessment of the quality of the biopsy material.

The microarray process and strategy for disclosing all the cartilage relevant genes with the above-mentioned tissues and cell culture criteria will be described in the following. An important issue of the inovative strategy used by the inventors of the present inventions is to use various microarrays containing a high number of genes comprising different functional categories preferentially by representing the whole genome. The broader the microarray regarding the coverage of the human genome the more genes associated with chondrocyte cell cultures can be determined. The chosen strategy of the inventors was not obvious to a person skilled in the art.

RNA isolated from the above mentioned different cell cultures conditions may be radioactive labeled with e.g. 33P or fluorescence like e.g. Cy3 and hybridized to the corresponding filters or microarrays. After hybridization each array may then be scanned and the corresponding signals measured (Tab IV). This raw data file needs then to be calibrated and normalized in a manner to create an input file for the further downstream analysis process. In principle if the data are normalized an expression profile is created. To identify the key cartilage marker genes being differentially expressed under the chosen criteria, tedious bioinformatic analysis are conducted. Corresponding cell cultures and their expression profiles are therefore compared and analyzed accordingly and the different clusters of marker genes determined by software analysis e.g. self-organizing maps (herein referred to as SOM). A representative example of a result for the comparison of different gene expression profiles from different cell culture conditions performed by SOM analysis is given in FIG. 1. By performing SOM analysis genes that are similarly expressed are clustered together in so-called sub clusters. The total amount of marker genes for one analysis corresponds to the total amount of sub clusters containing the corresponding genes. Table I in the appendix summarize the results of all the different analysis performed and encompasses all the genes determined for every set of cell culture analysis.

By performing this analytical procedure the analysis reveals several characteristic up and down regulated marker genes for different cellular culture conditions. From these marker genes characteristic expression profiles can then be deduced and used as a benchmark for the comparison or further characterization of other cell cultures.

Hence, on the one hand previously unknown cartilage—relevant genes associated with different culture conditions and on the other hand characteristic gene expression profiles (cellular fingerprints) indicative of a stage of development, a disease state or a particular selected cell culture condition are revealed. These fingerprints are part of the current invention and are of major importance for the classification and characterization of chondrocytes cultivated under different culture conditions.

Since the gene clusters from all the different analysis contain repetitive gene entries, they have been further processed so that only single entry genes are recorded (see Tab II). This 467 selected sequences are thus all key cartilage genes that are activated and thus differentially expressed according to a stage of development, a disease state or a particular selected cell culture condition and are part of the current invention. A list of all 467 genes with their Pubmed accession no. and a description is given below See also Tables II and III):

List of Table II Related Sequences: Pubmed Accesion No Description AA283693 Human osteoclast stimulating factor mRNA, complete cds AA845156 Serine protease inhibitor, Kazal type 1 R52548 Human superoxide dismutase (SOD-1) mRNA, complete cds T67128 ARYLAMINE N-ACETYLTRANSFERASE, MONOMORPHIC AA845015 Elastase 1, pancreatic (elastase IIA) AA937895 Antigen identified by monoclonal antibodies 12E7, F21 and O13 AA844998 Pancreatic polypeptide AA844818 Amylase, alpha 2A; pancreatic AA894557 Creatine kinase B AA872001 Annexin VI (p68) H09590 Human mRNA for eukaryotic initiation factor 4AI AA868278 Testis specific protein 1 (probe H4-1 p3-1) AA490855 Acid finger protein ZNF173 H05820 Human MRL3 mRNA for ribosomal protein L3 homologue (MRL3 = mammalian ribosome L3) N57766 Agammaglobulinaemia protein-tyrosine kinase atk AA873885 Alkaline phosphatase, liver/bone/kidney AA878880 Interferon (gamma)-induced cell line; protein 10 from R54818 Human eukaryotic initiation factor 2B-epsilon mRNA, partial cds AA458630 RENIN PRECURSOR, RENAL W37864 Phosphatase and tensin homolog (mutated in multiple advanced cancers 1) N63192 Phenylethanolamine N-methyltransferase R55789 Human X11 protein mRNA, partial cds R56871 Human chromatin assembly factor-I p60 subunit mRNA, complete cds AA448659 M-PHASE INDUCER PHOSPHATASE 2 AA235388 Tropomodulin W37769 Chromogranin B (secretogranin 1) AA421701 H. sapiens mRNA for MUF1 protein N81029 Collagen, type XVIII, alpha 1 AA644128 Nuclear autoantigenic sperm protein (histone-binding) N26536 ATPase, Cu++ transporting, beta polypeptide (Wilson disease) AA890663 Human protein kinase PAK1 mRNA, complete cds AA405987 Glycerol kinase 2 (testis specific) AA888182 Ribosomal protein S4, X-linked H09730 Adenylate kinase 2 (adk2) AA285155 CDC46 HOMOLOG AA873351 Ribosomal protein L35a H12320 CAMP-RESPONSE ELEMENT BINDING PROTEIN AA856556 Ribosomal protein S28 R43581 Human guanine nucleotide-binding protein G-s, alpha subunit mRNA, partial cds AA633768 60S RIBOSOMAL PROTEIN L24 AA496880 Ribosomal protein L5 AA625632 Ubiquitin A-52 residue ribosomal protein fusion product 1 R40850 H. sapiens mRNA for alpha-centractin AA486072 Small inducible cytokine A5 (RANTES) N80129 Metallothionein 1L T67270 UBIQUINOL-CYTOCHROME C REDUCTASE COMPLEX SUBUNIT VI REQUIRING PROTEIN AA775364 60S RIBOSOMAL PROTEIN L30 AA464743 Ribosomal protein L21 AA663983 Triosephosphate isomerase 1 AA634008 40S RIBOSOMAL PROTEIN S23 AA683050 40S RIBOSOMAL PROTEIN S8 AA775874 60S RIBOSOMAL PROTEIN L18 AA029934 Integrin, alpha V (vitronectin receptor, alpha polypeptide, antigen CD51) AA872397 GALECTIN-2 AA428195 Protein tyrosine phosphatase, non-receptor type 2 AA478724 Insulin-like growth factor binding protein 6 T40541 H. sapiens mRNA for human giant larvae homolog N33214 H. sapiens mRNA for membrane-type matrix metalloproteinase 1 W69399 Homo sapiens adenosine triphosphatase mRNA, complete cds H85454 Homo sapiens delayed-rectifier K+ channel alpha subunit (KCNS1) mRNA, complete cds T71284 Complement component 1, q subcomponent, beta polypeptide N95418 Human FK-506 binding protein homologue (FKBP38) mRNA, complete cds AA430675 Human DNA repair protein XRCC9 (XRCC9) mRNA, complete cds AA682851 Homo sapiens mRNA for ERp28 protein AA427433 PROTEIN PHOSPHATASE PP2A, 65 KD REGULATORY SUBUNIT, ALPHA ISOFORM AA100296 H. sapiens PAP mRNA AA070997 Proteasome (prosome, macropain) subunit, beta type, 6 R27585 Proteasome component C2 N71628 Spi-B transcription factor (Spi-1/PU.1 related) AA464566 Human mRNA for LDL-receptor related protein AA043228 Calponin 3, acidic AA478273 APEX nuclease (multifunctional DNA repair enzyme) H05619 Homo sapiens GDNF family receptor alpha 2 (GFRalpha2) mRNA, complete cds AA405562 Protein phosphatase 4 (formerly X), catalytic subunit AA147043 Homo sapiens CAGH1a (CAGH1) mRNA, partial cds AA035384 Homo sapiens mRNA for small subunit of cytochrome b in succinate dehydrogenase complex, complete cds R60150 Human mRNA for histidyl-tRNA synthetase (HRS) N64051 Homo sapiens Werner syndrome gene, complete cds AA405748 SPLICING FACTOR U2AF 65 KD SUBUNIT AA461110 Homo sapiens growth-arrest-specific protein (gas) mRNA, complete cds AA845167 ELASTASE IIIA PRECURSOR AA443118 Homo sapiens mRNA for CD151, complete cds N92319 Glycoprotein Ib (platelet), beta polypeptide AA187148 Core-binding factor, beta subunit AA253413 Friedreich ataxia AA046701 ATP SYNTHASE LIPID-BINDING PROTEIN P1 PRECURSOR AA164562 Homo sapiens actin-related protein Arp3 (ARP3) mRNA, complete cds AA496357 Homo sapiens SKB1Hs mRNA, complete cds AA180742 TUBULIN ALPHA-4 CHAIN AA454743 Human protease M mRNA, complete cds AA437226 Interleukin 10 receptor AA458849 Homo sapiens placental bikunin mRNA, complete cds AA504891 Crystallin, alpha B AA609655 Homo sapiens mRNA for SCP-1, complete cds AA599158 MULTIFUNCTIONAL AMINOACYL-TRNA SYNTHETASE AA052932 Homo sapiens casein kinase I gamma 2 mRNA, complete cds AA789328 Homo sapiens (clone PK2J) CDC2-related protein kinase (PISSLRE) mRNA, complete cds AA129537 Human GAP SH3 binding protein mRNA, complete cds AA486209 Low density lipoprotein-related protein-associated protein 1 (alpha-2-macroglobulin receptor-associated protein 1 H39018 H. sapiens Syt V gene (genomic and cDNA sequence) AA464217 V-akt murine thymoma viral oncogene homolog 1 T95053 Homo sapiens Rigui (RIGUI) mRNA, complete cds AA454646 LYMPHOTOXIN-BETA RECEPTOR PRECURSOR AA448400 Human plectin (PLEC1) mRNA, complete cds H13691 Major histocompatibility complex, class II, DM beta AA132086 Homo sapiens RCL (Rcl) mRNA, complete cds AA488073 Mucin 1, transmembrane N40945 H. sapiens mRNA for DRES9 protein R55705 Homo sapiens orexin receptor-1 mRNA, complete cds H50114 Homo sapiens NMDA receptor mRNA, complete cds AA452841 Human K-CI cotransporter (hKCC1) mRNA, complete cds W73790 IMMUNOGLOBULIN-RELATED 14.1 PROTEIN PRECURSOR N30302 POSSIBLE GTP-BINDING PROTEIN HSR1 AA291556 Human ras inhibitor mRNA, 3′ end AA598510 Human APRT gene for adenine phosphoribosyltransferase AA453787 Human TFIIB related factor hBRF (HBRF) mRNA, complete cds H05655 Human transcriptional activator mRNA, complete cds AA419177 INTEGRAL MEMBRANE PROTEIN E16 AA458807 Human retinal protein (HRG4) mRNA, complete cds AA293218 Cleavage stimulation factor, 3′ pre-RNA, subunit 2, 64 kD W44860 Human calmodulin mRNA, complete cds AA629862 Homo sapiens mRNA for smallest subunit of ubiquinol-cytochrome c reductase, complete cds AA447674 Homo sapiens HIV-Nef associated acyl CoA thioesterase (hNAACTE) mRNA, complete cds T52484 Nerve growth factor beta AA496810 Protein kinase C substrate 80K-H AA486233 G1 to S phase transition 1 AA079775 TYROSINE-PROTEIN KINASE CSK W73889 Tetranectin (plasminogen-binding protein) R50337 Solute carrier family 19 (folate transporter), member 1 R55046 MpV17 transgene, murine homolog, glomerulosclerosis R46821 T-COMPLEX PROTEIN 1, ALPHA SUBUNIT R87763 Human telencephalin precursor mRNA, complete cds H69583 Human BTG2 (BTG2) mRNA, complete cds R56046 Guanine nucleotide binding protein (G protein), alpha z polypeptide AA922705 Glycogen phosphorylase B (brain form) AA487571 Surfactant, pulmonary-associated protein C AA402440 Homo sapiens exportin t mRNA, complete cds H29521 ATP-binding cassette 3 AA490911 Homo sapiens drp1 mRNA, complete cds AA486082 Homo sapiens sgk gene AA678065 2,3-bisphosphoglycerate mutase R43509 Human Gu binding protein mRNA, partial cds N57553 Adenosine receptor A2 AA676955 Aplysia ras-related homolog 12 R14692 Human Na/H antiporter (APNH1) mRNA, complete cds AA488979 Homo sapiens nucleolar protein (MSP58) mRNA, complete cds AA443630 Aldehyde dehydrogenase 8 AA027840 H. sapiens mRNA for RIT protein AA456830 Diacylglycerol kinase, alpha (80 kD) AA453015 H. sapiens L23-related mRNA AA074446 Human GTP cyclohydrolase I feedback regulatory protein gene, complete cds AA027042 DNA-DIRECTED RNA POLYMERASE II 23 KD POLYPEPTIDE AA629923 Human mRNA for pM5 protein AA460830 Homo sapiens (clone mf.18) RNA polymerase II mRNA, complete cds AA454218 Homo sapiens transcription factor SL1 mRNA, complete cds AA046523 H. sapiens mRNA for centrin gene R51346 Human eIF-2-associated p67 homolog mRNA, complete cds AA029964 Human ataxin-2 related protein mRNA, partial cds AA489219 DUTP pyrophosphatase AA043133 Solute carrier family 16 (monocarboxylic acid transporters), member 1 AA812973 Human mRNA for testis-specific TCP20, complete cds AA453471 GANGLIOSIDE GM2 ACTIVATOR PRECURSOR AA284693 Transcription factor AP-4 (activating enhancer-binding protein 4) N90281 Human B7 mRNA, complete cds AA629542 Brush-1 AA679345 Human BTK region clone ftp-3 mRNA H37774 Tuberin T97181 Platelet factor 4 AA454879 Plasminogen activator, urokinase receptor AA147640 Phosphorylase, glycogen; liver (Hers disease, glycogen storage disease type VI) AA757429 Human serotonin N-acetyltransferase mRNA, complete cds AA490991 Homo sapiens HnRNP F protein mRNA, complete cds AA422058 H. sapiens mRNA for D1075-like gene N66208 Human (ard-1) mRNA, complete cds AA630776 Human AP-3 complex delta subunit mRNA, complete cds AA827287 Human interferon-induced leucine zipper protein (IFP35) mRNA, partial cds AA488084 Superoxide dismutase 2, mitochondrial R89715 Protein kinase C, gamma AA490501 H. sapiens mRNA; UV Radiation Resistance Associated Gene N32199 Human melanoma antigen recognized by T-cells (MART-1) mRNA AA434404 DNA primase polypeptide 2A (58 kD) N93686 Aldehyde dehydrogenase 7 AA292676 Human metargidin precursor mRNA, complete cds AA464417 INTERFERON-INDUCIBLE PROTEIN 1-8U AA442092 Catenin (cadherin-associated protein), beta 1 (88 kD) AA026644 Transcription factor 3 (E2A immunoglobulin enhancer binding factors E12/E47) AA481464 Peptidylprolyl isomerase B (cyclophilin B) T68859 Alpha-2-plasmin inhibitor (alpha-2-PI) AA699560 Surfeit 1 AA705069 Human mRNA for receptor of retinoic acid AA457739 Homo sapiens putative OSP like protein mRNA, partial cds H99843 Homo sapiens mRNA for quinolinate phosphoribosyl transferase, complete cds AA399410 Signal transducer and activator of transcription 3 (acute-phase response factor) AA443039 HEAT SHOCK 70 KD PROTEIN 1 AA164440 Human autoantigen pericentriol material 1 (PCM-1) mRNA, complete cds AA446453 Human mRNA for c-myc binding protein, complete cds AA280692 Diacylglycerol kinase delta AA031514 Matrix metalloproteinase 7 (matrilysin, uterine) R33154 Msh (Drosophila) homeo box homolog 1 (formerly homeo box 7) AA487452 Human DNA fragmentation factor-45 mRNA, complete cds AA400329 Human gene for neurofilament subunit M (NF-M) AA454668 Prostaglandin-endoperoxide synthase 1 (prostaglandin G/H synthase and cyclooxygenase) AA486393 Cytokine receptor family II, member 4 R52541 unknown EST AA171613 Homo sapiens carbonic anhydrase precursor (CA 12) mRNA, complete cds AA235706 Human TATA-binding protein associated factor 30 kDa subunit (tafII30) mRNA, complete cds AA668527 Human mucosal addressin cell adhesion molecule-1 (MAdCAM-1) mRNA, complete cds T54144 Homo sapiens homolog of the Aspergillus nidulans sudD gene product mRNA, complete cds R14080 Calcium modulating ligand AA609599 Homo sapiens SSX3 (SSX3) mRNA, complete cds AA489201 H. sapiens mRNA for PHAPI2b protein R08876 Human 26S proteasome-associated pad1 homolog (POH1) mRNA, complete cds H46425 H. sapiens Pur (pur-alpha) mRNA, complete cds R56149 Human putative transmembrane protein (nma) mRNA, complete cds AA454619 Homo sapiens mRNA for Hic-5, partial cds H15445 H. sapiens mRNA for SEX gene AA705225 Myosin, light polypeptide 4, alkali; atrial, embryonic AA191488 Human high-affinity copper uptake protein (hCTR1) mRNA, complete cds N64862 Human SLP-76 associated protein mRNA, complete cds R45413 Human transmembrane 4 superfamily protein (SAS) mRNA, complete cds R77293 Intercellular adhesion molecule 1 (CD54), human rhinovirus receptor AA436187 Integrin, alpha M (complement component receptor 3, alpha; also known as CD11b (p170), macrophage antigen alpha polypeptide) AA676470 H. sapiens IAI.3B mRNA AA443634 Homo sapiens ubiquitin conjugating enzyme G2 (UBE2G2) mRNA, complete cds AA664180 Glutathione peroxidase 3 (plasma) W58658 H. sapiens mRNA for CLPP H54023 Homo sapiens monocyte/macrophage Ig-related receptor MIR-10 (MIR cl-10) mRNA, complete cds H73724 Cyclin-dependent kinase 6 T70031 Human neutral amino acid transporter B mRNA, complete cds AA481758 DNAJ PROTEIN HOMOLOG 1 AA521431 Human profilin mRNA, complete cds AA446103 ERGIC-53 PROTEIN PRECURSOR N92646 Immunoglobulin gamma 3 (Gm marker) AA453789 Protein-tyrosine kinase 7 AA425299 Homo sapiens ezrin-radixin-moesin binding phosphoprotein-50 mRNA, complete cds AA868929 Troponin T1, skeletal, slow R60019 Homolog 2 of Drosophila large discs AA857343 Human putative RNA binding protein (RBP56) mRNA, complete cds AA481438 Complement component 1 inhibitor (angioedema, hereditary) AA399674 Human small proline rich protein (sprII) mRNA, clone 1292 T98887 Glucose-6-phosphatase AA676404 Peptidylprolyl isomerase C (cyclophilin C) H15747 Human HU-K4 mRNA, complete cds H16958 Human glyceraldehyde 3-phosphate dehydrogenase mRNA AA936783 Eukaryotic translation initiation factor 3 (eIF-3) p36 subunit AA884709 Cytochrome P450 11 beta H24688 Human SWI/SNF complex 170 KDa subunit (BAF170) mRNA, complete cds AA884403 Human cardiotrophin-1 (CTF1) mRNA, complete cds AA404619 5′ nucleotidase (CD73) AA598611 IMMEDIATE-EARLY RESPONSE PROTEIN NOT H72875 GATA-binding protein 3 H63361 Eukaryotic translation initiation factor 2B (eIF-2B) alpha subunit R39221 Human MAP kinase mRNA, complete cds R02346 U1 snRNP 70K protein R51835 unknown EST R33031 H. sapiens mRNA for sigma 3B protein AA412053 CD9 antigen AA001897 Erythroid alpha-spectrin W81191 Homo sapiens nucleolar autoantigen No55 mRNA, complete cds AA430552 Homo sapiens proline-rich Gla protein 2 (PRGP2) mRNA, complete cds AA394130 Human transducin-like protein mRNA, complete cds N92864 Human cleavage and polyadenylation specificity factor mRNA, complete cds AA457123 VALYL-TRNA SYNTHETASE R43320 Human guanine nucleotide-binding regulatory protein (Go-alpha) gene AA670430 Glutamate receptor, metabotropic 3 H65066 Visinin-like 1 AA458785 GUANYLATE CYCLASE SOLUBLE, BETA-1 CHAIN AA485871 H. sapiens mRNA for myosin-I beta T39411 Human 53K isoform of Type II phosphatidylinositol-4-phosphate 5-kinase (PIPK) mRNA, complete cds R00855 Homo sapiens 59 protein mRNA, 3′ end H98666 Metallopeptidase 1 (33 kD) H72028 GELSOLIN PRECURSOR, PLASMA AA679177 Human follistatin-related protein precursor mRNA, complete cds N21576 Human mitochondrial 1,25-dihydroxyvitamin D3 24-hydroxylase mRNA, complete cds AA007419 Human RGP4 mRNA, complete cds T49657 Homo sapiens TWIK-related acid-sensitive K+ channel (TASK) mRNA, complete cds N38959 Homo sapiens chaperonin containing t-complex polypeptide 1, beta subunit (Cctb) mRNA, complete cds R51912 Human somatostatin I gene and flanks H90415 Breast cancer 1, early onset H41489 Adaptin, beta 1 (beta prime) H15456 CALPAIN 1, LARGE W45415 ELASTASE IIIB PRECURSOR AA447751 Tyrosine hydroxylase AA487486 Cyclin D1 (PRAD1; parathyroid adenomatosis 1) R56604 Cholinergic receptor, nicotinic, alpha polypeptide 4 T65772 pulmonary surfactant protein (SP5) H15085 ADP-ribosylation factor 4-like R61295 Human ADP/ATP translocase mRNA, 3′ end, clone pHAT8 T61256 H. sapiens KHK mRNA for ketohexokinase, clone pHKHK3a AA405731 Phosphoenolpyruvate carboxykinase 1 (soluble) T71879 Complement component C2 R59927 Human mRNA for cytochrome c oxidase subunit VIc AA496780 Human small GTP binding protein Rab7 mRNA, complete cds AA176688 Human mRNA for lysosomal sialoglycoprotein, complete cds AA436163 Homo sapiens Pig12 (PIG12) mRNA, complete cds AA428778 Human placenta LERK-2 (EPLG2) mRNA, complete cds AA463225 Bone morphogenetic protein 4 AA485426 Interferon (alpha, beta and omega) receptor 2 W47485 Human sigma receptor mRNA, complete cds H84982 Human checkpoint suppressor 1 mRNA, complete cds AA504615 Homo sapiens mRNA for CAB1, complete cds H94487 Cathepsin E AA448959 Homo sapiens NADH: ubiquinone oxidoreductase 15 kDa IP subunit mRNA, nuclear gene encoding mitochondrial protein, complete cds AA070358 Transketolase (Wernicke-Korsakoff syndrome) AA453401 Human PH-20 homolog (LUCA2) mRNA, partial cds N66737 Collagen, type II, alpha 1 (primary osteoarthritis, spondyloepiphyseal dysplasia, congenital) AA666180 Human v-erbA related ear-2 gene AA857131 Human Tat-SF1 mRNA, complete cds AA479102 Protein kinase C, beta 1 AA456077 Homo sapiens mRNA for p27, complete cds R87497 H. sapiens mRNA for 2.19 gene AA718910 Human tax1-binding protein TXBP181 mRNA, complete cds AA406269 Nuclear factor I/X (CCAAT-binding transcription factor) N74623 Insulin-like growth factor 2 (somatomedin A) H99364 Human chloride channel protein (CLCN7) mRNA, partial cds AA447684 Small proline-rich protein 1B (cornifin) AA282301 Homo sapiens nuclear dual-specificity phosphatase (SBF1) mRNA, partial cds H99588 Human lymphoid nuclear protein (LAF-4) mRNA, complete cds N53512 Homo sapiens alpha 2 delta calcium channel subunit isoform I mRNA, complete cds AA683321 Homo sapiens PAR-5 mRNA, probable 5′ end AA608557 Damage-specific DNA binding protein 1 (127 kD) AA757764 Homo sapiens mRNA for DNA-binding protein, complete cds AA406064 Homo sapiens testis-specific Basic Protein Y 1 (BPY1) mRNA, complete cds N54596 Human Krueppel-related zinc finger protein (H-plk) mRNA, complete cds AA481988 Transcription factor 7 (T-cell specific) N62394 Gap junction protein, beta 1, 32 kD (connexin 32, Charcot-Marie-Tooth neuropathy, X- linked) N26148 Zinc finger protein 148 (pHZ-52) AA496678 B-cell CLL/lymphoma 3 AA400973 NEUTROPHIL GELATINASE-ASSOCIATED LIPOCALIN PRECURSOR AA497027 Human mRNA, clone HH109 (screened by the monoclonal antibody of insulin receptor substrate-1 (IRS-1)) N64508 Homo sapiens podocalyxin-like protein mRNA, complete cds AA033564 H. sapiens mRNA for DGCR6 protein AA446108 Endoglin (Osler-Rendu-Weber syndrome 1) AA159577 Mucin 5, subtype B, tracheobronchial R36958 unknown EST AA629808 Ribosomal protein L6 AA482067 Human tazarotene-induced gene 2 (TIG2) mRNA, complete cds AA669314 ATP synthase, H+ transporting, mitochondrial F1 complex, delta subunit AA775241 Aldolase A R73584 Homo sapiens hydroxysteroid sulfotransferase SULT2B1a (HSST2) mRNA, complete cds H28984 PHOSPHATIDYLSERINE SYNTHASE I R44202 Homo sapiens catechol-O-methyltransferase (COMT) mRNA, complete cds W70051 H. sapiens mRNA for M-phase phosphoprotein, mpp9 AA401972 Human RalGDS-like 2 (RGL2) mRNA, partial cds AA236164 CATHEPSIN S PRECURSOR R22412 Platelet/endothelial cell adhesion molecule (CD31 antigen) AA424804 MULTIDRUG RESISTANCE-ASSOCIATED PROTEIN 1 AA669443 Eukaryotic translation initiation factor 5 (elF5) N69689 RAS-RELATED PROTEIN RAB-1A H24316 AQUAPORIN-CHIP AA074224 Recoverin R36571 Human U1 snRNP-specific protein A gene AA056465 Human 54 kDa protein mRNA, complete cds AA633811 H. sapiens E4BP4 gene AA457155 Human zinc-finger protein C2H2-150 mRNA, complete cds AA459104 60S RIBOSOMAL PROTEIN L13 R40212 Human coatomer protein (HEPCOP) mRNA, complete cds AA086476 Adenosine monophosphate deaminase 1 (isoform M) AA663310 Thymidylate synthase AA455640 Homo sapiens signalosome subunit 3 (Sgn3) mRNA, complete cds AA496879 Human (clone E5.1) RNA-binding protein mRNA, complete cds AA085749 Homo sapiens mRNA for ATP binding protein, complete cds AA425755 Homo sapiens mRNA for leukemia associated gene 1 N52350 H. sapiens mRNA for protein-tyrosine-phosphatase (tissue type: testis) AA630104 Lipase A, lysosomal acid, cholesterol esterase (Wolman disease) AA454854 ALPHA-AMYLASE 2B PRECURSOR W73406 DIHYDROPRYRIDINE-SENSITIVE L-TYPE, SKELETAL MUSCLE CALCIUM CHANNEL GAMMA SUBUNIT R12802 Human cytochrome bc-1 complex core protein II mRNA, complete cds AA465355 Homo sapiens mRNA for U3 snoRNP associated 55 kDa protein AA829383 DUAL SPECIFICITY MITOGEN-ACTIVATED PROTEIN KINASE KINASE 3 AA629189 Keratin 4 AA430512 Homo sapiens cytoplasmic antiproteinase 3 (CAP3) mRNA, complete cds AA456439 Human homozygous deletion target in pancreatic carcinoma (DPC4) mRNA, complete cds H27864 SECRETOGRANIN II PRECURSOR AA644657 MHC class I protein HLA-A (HLA-A28, -B40, -Cw3) R40460 Homo sapiens phosphatidylinositol 4-kinase mRNA, complete cds W96058 Human hnRNP H mRNA, complete cds T72202 Human transcription factor IL-4 Stat mRNA, complete cds AA598794 Connective tissue growth factor AA599178 Ribosomal protein L27a R88247 Adrenergic, beta, receptor kinase 1 T98612 Alpha-1 type 3 collagen AA454856 Phospholipid hydroperoxide glutathione peroxidase N67048 Type 3 iodothyronine deiodinase AA778675 Homo sapiens mRNA for calmegin, complete cds H51117 Human calmodulin dependent phosphodiesterase PDE1B1 mRNA, complete cds N36174 5-HYDROXYTRYPTAMINE 2B RECEPTOR AA777187 Homo sapiens Cyr61 mRNA, complete cds R09561 Decay accelerating factor for complement (CD55, Cromer blood group system) R16849 Human HsPex13p mRNA, complete cds AA884167 ANNEXIN XIII AA136983 Cadherin 11 (OB-cadherin) AA488622 Human signal transducing adaptor molecule STAM mRNA, complete cds AA699427 Fructose-bisphosphatase 1 AA490459 Transcobalamin II AA626787 Human ras-related C3 botulinum toxin substrate (rac) mRNA, complete cds N62179 Human methylmalonate semialdehyde dehydrogenase gene, complete cds N27190 UBIQUITIN CARBOXYL-TERMINAL HYDROLASE ISOZYME L3 AA441895 Human glutathione-S-transferase homolog mRNA, complete cds AA463924 FACTOR VIII INTRON 22 PROTEIN N78843 Homo sapiens cyclophilin-33A (CYP-33) mRNA, complete cds AA629719 Cytochrome c oxidase VIIc subunit AA464755 Ankyrin 1, erythrocytic AA459351 H. sapiens sds22-like mRNA AA488346 MYOSIN LIGHT CHAIN ALKALI, SMOOTH-MUSCLE ISOFORM AA427899 Human mRNA fragment encoding beta-tubulin. (from clone D-beta-1) AA453813 H. sapiens mRNA for Gal-beta(1-3/1-4)GlcNAc alpha-2.3-sialyltransferase AA397824 Dopachrome tautomerase (dopachrome delta-isomerase, tyrosine-related protein 2) AA633901 Transforming growth factor, beta-induced, 68 kD AA181334 Troponin I (skeletal fast) AA292410 Clusterin (complement lysis inhibitor; testosterone-repressed prostate message 2; apolipoprotein J) AA253434 HEAT SHOCK FACTOR PROTEIN 2 AA455056 H. sapiens mRNA for MAP kinase activated protein kinase R55188 Human pre-T/NK cell associated protein (3B3) mRNA, 3′ end AA465723 Homo sapiens mRNA for protein phosphatase 2C gamma N49856 SODIUM-AND CHLORIDE-DEPENDENT BETAINE TRANSPORTER AA455272 H. sapiens mRNA for ITBA1 protein AA459292 CDC28 protein kinase 1 AA878561 Ubiquitin A-52 residue ribosomal protein fusion product 1 AA772066 Human phosphatidylinositol (4,5)bisphosphate 5-phosphatase homolog mRNA, partial cds N78621 H. sapiens mRNA for gamma-adaptin AA291490 H. sapiens mRNA for processing a-glucosidase I N46828 Homo sapiens mRNA for inositol 1,4,5-trisphosphate 3-kinase isoenzyme, partial cds AA150487 Alkaline phosphatase, placental (Regan isozyme) AA282537 MYOCYTE-SPECIFIC ENHANCER FACTOR 2 AA707922 Human mRNA for cone-specific cGMP phosphodiesterase gamma subunit, complete cds AA443638 Homo sapiens breast cancer-specific protein 1 (BCSG1) mRNA, complete cds W73892 Human putative tumor suppressor (LUCA15) mRNA, complete cds N70734 Troponin T2 (cardiac) H57136 Human phospholemman chloride channel mRNA, complete cds AA709414 Nidogen (enactin) W65461 Human protein tyrosine phosphatase mRNA, complete cds AA436564 Human cellular proto-oncogene (c-mer) mRNA, complete cds AA029042 Human hSIAH2 mRNA, complete cds AA427725 Homo sapiens carboxypeptidase Z precursor, mRNA, complete cds N51280 ADP-ribosylation factor like 1 AA281347 H. sapiens mRNA for MHC class I promoter binding protein AA402960 Human HLA class III region containing NOTCH4 gene, partial sequence, homeobox PBX2 (HPBX) gene, receptor for advanced glycosylation end products (RAGE) gene, complete cds, and 6 unidentified cds N98485 Human forkhead protein FREAC-2 mRNA, partial cds AA490209 H. sapiens mRNA for Sop2p-like protein W61361 Homo sapiens cytoplasmic antiproteinase 2 (CAP2) mRNA, complete cds N51018 Biglycan AA455281 DEFENDER AGAINST CELL DEATH 1 W69471 V-ski avian sarcoma viral oncogene homolog AA486321 Vimentin AA458982 Solute carrier family 9 (sodium/hydrogen exchanger), isoform 1 (antiporter, Na+/H+, amiloride sensitive) AA442095 NEDD-4 PROTEIN N99003 Active BCR-related gene AA609284 Homo sapiens mRNA for Eph-family protein, complete cds AA195036 Human Ro/SSA ribonucleoprotein homolog (RoRet) mRNA, complete cds AA478268 Human CtBP mRNA, complete cds AA608583 Homo sapiens mRNA for OTK27, complete cds AA486435 Homo sapiens mRNA for CDEP, complete cds AA505045 Human L2-9 transcript of unrearranged immunoglobulin V(H)5 pseudogene AA487893 TUMOR-ASSOCIATED ANTIGEN L6 AA292226 Homo sapiens creatine transporter mRNA, complete cds H87106 Homo sapiens T245 protein (T245) mRNA, complete cds W96450 Human putative tRNA synthetase-like protein mRNA, complete cds N33331 Human peroxisome proliferator activated receptor mRNA, complete cds AA405800 Dodecenoyl-Coenzyme A delta isomerase (3,2 trans-enoyl-Coenzyme A isomerase) T51539 Macrophage stimulating 1 (hepatocyte growth factor-like) N59764 Human guanosine 5′-monophosphate synthase mRNA, complete cds AA521346 H. sapiens mRNA for Ndr protein kinase AA428551 Homo sapiens SOX22 protein (SOX22) mRNA, complete cds AA489383 Bone morphogenetic protein 2 AA490172 Collagen, type I, alpha-2 AA504477 Human cytoskeleton associated protein (CG22) mRNA, complete cds

List of Table III related sequences: Accession_(—) mrgd NAME Gene M98539 Human prostaglandin D2 synthase gene, exon 7 AB004922 Homo sapiens gene for Smad 3, exon 1, partial sequence AB006000 Homo sapiens mRNA for chondromodulin-I precursor, complete cds AB017364 Homo sapiens mRNA for frizzled-2, complete cds AB020236 Homo sapiens gene for ribosomal protein L27A, complete cds Ribosomal protein L27a AB042820 Homo sapiens RPL6 gene for ribosomal protein L6, complete cds Ribosomal protein L6 AB043547 Homo sapiens gene for SMAD4, partial cds AB080265 Homo sapiens CYP2J2 mRNA for cytochrome P450 2J2, complete cds Cytochrome P450, subfamily IIJ (arachidonic acid epoxygenase) polypeptide 2 AF000979 Homo sapiens testis-specific Basic Protein Y 1 (BPY1) mRNA, complete cds Homo sapiens testis-specific Basic Protein Y 1 (BPY1) mRNA, complete cds AF001450 Homo sapiens core binding factor alpha1 subunit (CBFA1) gene, exon 7 and complete cds AF004231 Homo sapiens monocyte/macrophage Ig-related receptor MIR-10 (MIR cl-10) Homo sapiens monocyte/macrophage Ig-related mRNA, complete cds receptor MIR-10 (MIR cl-10) mRNA, complete cds AF009801 Homo sapiens homeodomain protein (BAPX1) mRNA, complete cds AF010126 Homo sapiens breast cancer-specific protein 1 (BCSG1) mRNA, complete cds Homo sapiens breast cancer-specific protein 1 (BCSG1) mRNA, complete cds AF010316 Homo sapiens Pig12 (PIG12) mRNA, complete cds Homo sapiens Pig12 (PIG12) mRNA, complete cds AF013591 Homo sapiens homolog of the Aspergillus nidulans sudD gene product mRNA, Homo sapiens homolog of the complete cds Aspergillus nidulans sudD gene product mRNA, complete cds AF037204 Homo sapiens RING zinc finger protein (RZF) mRNA, complete cds AF043339 Homo sapiens macrophage inflammatory protein 1 alpha (MIP1a) mRNA, partial cds AF049656 Homo sapiens inducible nitric oxide synthase (iNOS) mRNA, complete cds AF072872 Homo sapiens frizzled 1 mRNA, complete cds AF188285 Homo sapiens bone morphogenetic protein 9 (BMP9) mRNA, complete cds AF189279 Homo sapiens group IIE secretory phospholipase A2 mRNA, complete cds AF248634 Homo sapiens syndecan 3 (SDC3) mRNA, complete cds AF304431 Homo sapiens hypoxia-inducible factor 1 alpha subunit (HIF1A) mRNA, complete cds AF339054 Homo sapiens BCL2-associated X protein (BAX) gene, exons 1, 2 and partial cds AF348700 Homo sapiens ubiquitin A-52 residue ribosomal protein fusion product 1 Ubiquitin A-52 residue ribosomal protein (UBA52), mRNA, complete cds fusion product 1 AF395008 Homo sapiens interleukin 4 (IL4) gene, complete cds AF405705 Homo sapiens matrix metalloproteinase 3 (stromelysin 1, progelatinase) (MMP3) gene, complete cds AF411526 Homo sapiens nerve growth factor beta (NGFB) mRNA, complete cds Nerve growth factor beta AF469046 Homo sapiens macrophage migration inhibitory factor (MIF) mRNA, complete cds AF477981 Homo sapiens osterix mRNA, complete cds AJ279016 Homo sapiens mRNA for chondrocyte expressed protein 68 kDa (CEP-68 gene) AY043326 Homo sapiens keratin 4 (KRT4) gene, complete cds Keratin 4 AY044847 Homo sapiens aggrecanase 1 (ADAMTS4) gene, complete cds D13748 Human mRNA for eukaryotic initiation factor 4AI Human mRNA for eukaryotic initiation factor 4AI D38255 Homo sapiens mRNA for CAB1, complete cds Homo sapiens mRNA for CAB1, complete cds D45399 Human mRNA for cone-specific cGMP phosphodiesterase gamma subunit, Human mRNA for cone-specific cGMP complete cds phosphodiesterase gamma subunit, complete cds D49738 Human cytoskeleton associated protein (CG22) mRNA, complete cds Human cytoskeleton associated protein (CG22) mRNA, complete cds D49835 Homo sapiens mRNA for DNA-binding protein, complete cds Homo sapiens mRNA for DNA-binding protein, complete cds D90040 Human mRNA for arylamine N-acetyltransferase (EC 2.3.1.5) ARYLAMINE N-ACETYLTRANSFERASE, MONOMORPHIC J00306 Human somatostatin I gene and flanks Human somatostatin I gene and flanks J03191 Human profilin mRNA, complete cds Human profilin mRNA, complete cds J03592 Human ADP/ATP translocase mRNA, 3′ end, clone pHAT8 Human ADP/ATP translocase mRNA, 3′ end, clone pHAT8 J04111 Human c-jun proto oncogene (JUN), complete cds, clone hCJ-1 J04177 Human alpha-1 type XI collagen (COL11A1) mRNA, complete cds J04973 Human cytochrome bc-1 complex core protein II mRNA, complete cds Human cytochrome bc-1 complex core protein II mRNA, complete cds J05036 Human cathepsin E mRNA, complete cds Cathepsin E K00065 Human superoxide dismutase (SOD-1) mRNA, complete cds Human superoxide dismutase (SOD-1) mRNA, complete cds K00650 Human fos proto-oncogene (c-fos), complete cds L05095 Homo sapiens ribosomal protein L30 mRNA, complete cds 60S RIBOSOMAL PROTEIN L30 L08895 Homo sapiens MADS/MEF2-family transcription factor (MEF2C) mRNA, complete cds L10347 Human pro-alpha1 type II collagen (COL2A1) gene exons 1-54, complete cds L11566 Homo sapiens ribosomal protein L18 (RPL18) mRNA, complete cds 60S RIBOSOMAL PROTEIN L18 L13286 Human mitochondrial 1,25-dihydroxyvitamin D3 24-hydroxylase mRNA, Human mitochondrial 1,25-dihydroxyvitamin complete cds D3 24-hydroxylase mRNA, complete cds L13463 Human helix-loop-helix basic phosphoprotein (G0S8) mRNA, complete cds L13616 Human focal adhesion kinase (FAK) mRNA, complete cds L13720 Homo sapiens growth-arrest-specific protein (gas) mRNA, complete cds Homo sapiens growth-arrest-specific protein (gas) mRNA, complete cds L22009 Human hnRNP H mRNA, complete cds Human hnRNP H mRNA, complete cds L28997 Homo sapiens ARL1 mRNA, complete cds ADP-ribosylation factor like 1 L31409 Homo sapiens creatine transporter mRNA, complete cds Homo sapiens creatine transporter mRNA, complete cds L33930 Homo sapiens CD24 signal transducer mRNA, complete cds and 3′ region L34059 Homo sapiens cadherin-4 mRNA, complete cds L41162 Homo sapiens collagen alpha 3 type IX (COL9A3) mRNA, complete cds L47647 Homo sapiens creatine kinase B mRNA, complete cds Creatine kinase B M13994 Human B-cell leukemia/lymphoma 2 (bcl-2) proto-oncogene mRNA encoding bcl-2-alpha protein, complete cds M14144 Human vimentin gene, complete cds Vimentin M14631 Human guanine nucleotide-binding protein G-s, alpha subunit mRNA, partial Human guanine nucleotide-binding protein G-s, cds alpha subunit mRNA, partial cds M16652 Human pancreatic elastase IIA mRNA, complete cds Elastase 1, pancreatic (elastase IIA) M20137 Human interleukin 3 (IL-3) mRNA, complete cds, clone pcD-SR-alpha M22636 Human U1 small nuclear ribonucleoprotein 70 kd protein mRNA, complete cds U1 snRNP 70K protein M37825 Human fibroblast growth factor-5 (FGF-5) mRNA, complete cds M57293 Human parathyroid hormone-related peptide (PTHRP) gene, exons 1A, 1B, 1C, and 2 M58458 Human ribosomal protein S4 (RPS4X) isoform mRNA, complete cds Ribosomal protein S4, X-linked M58525 Homo sapiens catechol-O-methyltransferase (COMT) mRNA, complete cds Homo sapiens catechol-O-methyltransferase (COMT) mRNA, complete cds M58549 Human matrix Gla protein (MGP) mRNA, complete cds M61877 Human erythroid alpha-spectrin (SPTA1) mRNA, complete cds Erythroid alpha-spectrin M62402 Human insulin-like growth factor binding protein 6 (IGFBP6) mRNA, complete Insulin-like growth factor binding protein 6 cds M65062 Human insulin-like growth factor binding protein 5 (IGFBP-5) mRNA, complete cds M65217 Human heat shock factor 2 (HSF2) mRNA, complete cds HEAT SHOCK FACTOR PROTEIN 2 M76701 Homo sapiens zinc finger protein 35 (ZNF35) gene, exon 1 M77016 Human tropomodulin mRNA, complete cds Tropomodulin M81768 Human Na/H antiporter (APNH1) mRNA, complete cds Human Na/H antiporter (APNH1) mRNA, complete cds M84489 Human extracellular signal-regulated kinase 2 mRNA, complete cds M84721 Human AMP deaminase (AMPD3) mRNA, complete cds Adenosine monophosphate deaminase (isoform E) M87842 Human S-lac lectin L-14-II (LGALS2) mRNA, complete cds GALECTIN-2 M92934 Human connective tissue growth factor, complete cds Connective tissue growth factor M95610 Human alpha 2 type IX collagen (COL9A2) mRNA, partial cds M96684 H. sapiens Pur (pur-alpha) mRNA, complete cds H. sapiens Pur (pur-alpha) mRNA, complete cds M97676 Homo sapiens (region 7) homeobox protein (HOX7) mRNA, complete cds NM_000194 Homo sapiens hypoxanthine phosphoribosyltransferase 1 (Lesch-Nyhan syndrome) (HPRT1), mRNA NM_000213 Homo sapiens integrin, beta 4 (ITGB4), mRNA NM_000221 Homo sapiens ketohexokinase (fructokinase) (KHK), transcript variant a, H. sapiens KHK mRNA for ketohexokinase, mRNA clone pHKHK3a NM_000235 Homo sapiens lipase A, lysosomal acid, cholesterol esterase (Wolman Lipase A, lysosomal acid, cholesterol esterase disease) (LIPA), mRNA (Wolman disease) NM_000358 Homo sapiens transforming growth factor, beta-induced, 68 kD (TGFBI), mRNA Transforming growth factor, beta-induced, 68 kD NM_000364 Homo sapiens troponin T2, cardiac (TNNT2), mRNA Troponin T2 (cardiac) NM_000537 Homo sapiens renin (REN), mRNA RENIN PRECURSOR, RENAL NM_000574 Homo sapiens decay accelerating factor for complement (CD55, Cromer blood Decay accelerating factor for complement group system) (DAF), mRNA (CD55, Cromer blood group system) NM_000600 Homo sapiens interleukin 6 (interferon, beta 2) (IL6), mRNA NM_000618 Homo sapiens insulin-like growth factor 1 (somatomedia C) (IGF1), mRNA NM_000632 Homo sapiens Integrin, alpha M (complement component receptor 3, alpha; Integrin, alpha M (complement component also known as CD11b (p170), macrophage antigen alpha polypeptide) receptor 3, alpha; also known as CD11b (ITGAM), mRNA (p170), polypeptide) macrophage antigen alpha NM_000711 Homo sapiens bone gamma-carboxyglutamate (gla) protein (osteocalcin) (BGLAP), mRNA NM_000962 Homo sapiens prostaglandin-endoperoxide synthase 1 (prostaglandin G/H Prostaglandin-endoperoxide synthase 1 synthase and cyclooxygenase) (PTGS1), transcript variant 1, mRNA (prostaglandin G/H synthase and cyclooxygenase) MM_000977 Homo sapiens ribosomal protein L13 (RPL13), transcript variant 1, mRNA 60S RIBOSOMAL PROTEIN L13 NM_000996 Homo sapiens ribosomal protein L35a (RPL35A), mRNA Ribosomal protein L35a NM_001012 Homo sapiens ribosomal protein S8 (RPS8), mRNA 40S RIBOSOMAL PROTEIN S8 NM_001025 Homo sapiens ribosomal protein S23 (RPS23), mRNA 40S RIBOSOMAL PROTEIN S23 NM_001064 Homo sapiens transketolase (Wernicke-Korsakoff syndrome) (TKT), mRNA Transketolase (Wernicke-Korsakoff syndrome) NM_001127 Homo sapiens adaptor-related protein complex 1, beta 1 subunit Adaptin, beta 1 (beta prime) AP1B1), mRNA NM_001200 Homo sapiens bone morphogenetic protein 2 (BMP2), mRNA Bone morphogenetic protein 2 NM_001229 Homo sapiens caspase 9, apoptosis-related cysteine protease (CASP9), transcript variant alpha, mRNA NM_001511 Homo sapiens GRO1 oncogene (melanoma growth stimulating activity, alpha) (GRO1), mRNA NM_001565 Homo sapiens small inducible cytokine subfamily B (Cys-X-Cys), member 10 Interferon (gamma)-induced cell line; (SCYB10), mRNA protein 10 from NM_001632 Homo sapiens alkaline phosphatase, placental (Regan isozyme) (ALPP), Alkaline phosphatase, placental mRNA (Regan isozyme) NM_001687 Homo sapiens ATP synthase, H+ transporting, mitochondrial F1 complex, delta ATP synthase, H+ transporting, subunit (ATP5D), mRNA mitochondrial F1 complex, delta subunit NM_001718 Homo sapiens bone morphogenetic protein 6 (BMP6), mRNA NM_001745 Homo sapiens calcium modulating ligand (CAMLG), mRNA Calcium modulating ligand NM_001797 Homo sapiens cadherin 11, type 2, OB-cadherin (osteoblast) (CDH11), transcript variant 1, mRNA NM_001844 Homo sapiens collagen, type II, alpha 1 (primary osteoarthritis, spondyloepiphyseal dysplasia, congenital) (COL2A1), transcript variant 1, mRNA NM_001912 Homo sapiens cathepsin L (CTSL), mRNA NM_001969 Homo sapiens eukaryotic translation initiation factor 5 (EIF5), mRNA Eukaryotic translation initiation factor 5 (eIF5) NM_002073 Homo sapiens guanine nucleotide binding protein (G protein), alpha z Guanine nucleotide binding protein polypeptide (GNAZ), mRNA polypeptide (G protein), alpha z NM_002094 Homo sapiens G1 to S phase transition 1 (GSPT1), mRNA G1 to S phase transition 1 NM_002160 Homo sapiens hexabrachion (tenascin C, cytotactin) (HXB), mRNA NM_002211 Homo sapiens integrin, beta 1 (fibronectin receptor, beta polypeptide, antigen CD29 includes MDF2, MSK12) (ITGB1), mRNA NM_002379 Homo sapiens matrilin 1, cartilage matrix protein (MATN1), mRNA NM_002381 Homo sapiens matrilin 3 (MATN3) precursor, mRNA NM_002421 Homo sapiens matrix metalloproteinase 1 (interstitial collagenase) (MMP1), mRNA NM_002424 Homo sapiens matrix metalloproteinase 8 (neutrophil collagenase) (MMP8), mRNA NM_002427 Home sapiens matrix metalloproteinase 13 (collagenase 3) (MMP13), mRNA NM_002591 Homo sapiens phosphoenolpyruvate carboxykinase 1 (soluble) (PCK1), mRNA Phosphoenolpyruvate carboxykinase 1 (soluble) mRNA carboxykinase 1 (soluble) NM_002619 Home sapiens platelet factor 4 (PF4), mRNA Platelet factor 4 NM_002722 Homo sapiens pancreatic polypeptide (PPY), mRNA NM_002738 Homo sapiens protein kinase C, beta 1 (PRKCB1), mRNA Protein kinase C, beta 1 NM_002903 Homo sapiens recoverin (RCV1), mRNA Recoverin NM_003036 Homo sapiens v-ski sarcoma viral oncogene homolog (avian) (SKI), mRNA V-ski avian sarcoma viral oncogene homolog NM_003282 Homo sapiens troponin I, skeletal, fast (TNNI2), mRNA Troponin I (skeletal fast) NM_003385 Homo sapiens visinin-like 1 (VSNL1), Visinin-like 1 NM_003395 Homo sapiens wingless-type MMTV integration site family, member 14 (WNT14), mRNA NM_004613 Homo sapiens transglutaminase 2 (C polypeptide, protein-glutamine-gamma-glutamyltransferase) (TGM2), mRNA NM_004832 Homo sapiens glutathione-S-transferase like; glutathione transferase omega Human glutathione-S-transferase homolog (GSTTLp28), mRNA cds mRNA, complete NM_004994 Homo sapiens matrix metalloproteinase 9 (gelatinase B, 92 kD gelatinase, 92 kD type IV collagenase) (MMP9), mRNA NM_004995 Homo sapiens matrix metalloproteinase 14 (membrane-inserted) (MMP14), mRNA NM_005038 Homo sapiens peptidylprolyl isomerase D (cyclophilin D) (PPID), mRNA 40 KD PEPTIDYL-PROLYL CIS-TRANS ISOMERASE NM_005186 Homo sapiens calpain 1, (mu/l) large subunit (CAPN1), mRNA CALPAIN 1, LARGE NM_005346 Homo sapiens heat shock 70 kD protein 1B (HSPA1B), mRNA HEAT SHOCK 70 KD PROTEIN 1 NM_005438 Homo sapiens FOS-like antigen 1 (FOSL1), mRNA NM_005506 Homo sapiens CD36 antigen (collagen type I receptor, thrombospondin receptor)-like 2 (lysosomal integral membrane protein II) (CD36L2), mRNA NM_006289 Homo sapiens talin 1 (TLN1), mRNA NM_006988 Homo sapiens a disintegrin-like and metalloprotease (reprolysin type) with thrombospondin type 1 motif, 1 (ADAMTS1), mRNA NM_007306 Homo sapiens breast cancer 1, early onset (BRCA1), transcript variant Breast cancer 1, early onset BRCA1-exon4, mRNA NM_007352 Homo sapiens elastase 3B, pancreatic (ELA3B), Mrna ELASTASE IIIB PRECURSOR NM_014000 Homo sapiens vinculin (VCL), transcript variant meta-VCL, mRNA NM_014470 Homo sapiens GTP-binding protein (RHO6), mRNA NM_018952 Homo sapiens homeo box B6 (HOXB6), mRNA NM_021019 Homo sapiens myosin, light polypeptide 6, alkali, smooth muscle and non- MYOSIN LIGHT CHAIN ALKALI, muscle (MYL6), transcript variant 1, mRNA SMOOTH-MUSCLE ISOFORM NM_033150 Homo sapiens collagen, type II, alpha 1 (primary osteoarthritis, spondyloepiphyseal dysplasia, congenital) (COL2A1), transcript variant 2, mRNA NM_053056 Homo sapiens cyclin D1 (PRAD1: parathyroid adenomatosis 1) (CCND1), Cyclin D1 (PRAD1; parathyroid mRNA adenomatosis 1) NM_080682 Homo sapiens vascular cell adhesion molecule 1 (VCAM 1), transcript variant 2, mRNA S79854 Homo sapiens type 3 iodothyronine deiodinase mRNA, complete cds Type 3 iodothyronine deiodinase S83308 SOX5 = Sry-related HMG box gene {alternatively spliced} [human, testis, mRNA, 1473 nt] U07424 Human putative tRNA synthetase-like protein mRNA, complete cds Human putative tRNA synthetase-like protein mRNA, complete cds U07620 Human MAP kinase mRNA, complete cds Human MAP kinase mRNA, complete cds U08023 Human cellular proto-oncogene (c-mer) mRNA, complete cds Human cellular proto-oncogene (c-mer) mRNA, complete cds U09303 Human T cell leukemia LERK-2 (EPLG2) mRNA, complete cds U09577 Homo sapiens lysosomal hyaluronidase (LUCA2/HYAL2) mRNA, complete cds Human PH-20 homolog (LUCA2) mRNA, partial cds U09825 Human acid finger protein mRNA, complete cds Acid finger protein ZNF173 U13261 Homo sapiens eIF-2-associated p67 homolog mRNA, complete cds Human eIF-2-associated p67 homolog mRNA, complete cds U13660 Human cartilage-derived morphogenetic protein 1 (CDMP-1) mRNA, complete cds U13991 Human TATA-binding protein associated factor 30 kDa subunit (tafII30) mRNA, Human TATA-binding protein associated complete cds factor 30 kDa subunit (tafII30) mRNA, complete cds U14966 Human ribosomal protein L5 mRNA, complete cds Ribosomal protein L5 U14971 Human ribosomal protein S9 mRNA, complete cds U15085 Human HLA-DMB mRNA, complete cds Major histocompatibility complex, class II, DM beta U16031 Human transcription factor IL-4 Stat mRNA, complete cds Human transcription factor IL-4 Stat mRNA, complete cds U16261 Human MDA-7 (mda-7) mRNA, complete cds U18299 Human damage-specific DNA binding protein DDBa p127 subunit (DDB1) Damage-specific DNA binding protein mRNA, complete cds 1 (127 kD) U20980 Human chromatin assembly factor-I p60 subunit mRNA, complete cds Human chromatin assembly factor-I p60 subunit mRNA, complete cds U22409 Human parathyroid hormone/PTH-related peptide receptor (PTH/PTHrP) gene, exon 14 and complete cds U23028 Human eukaryotic initiation factor 2B-epsilon mRNA, partial cds Human eukaryotic initiation factor 2B-epsilon mRNA, partial cds U23946 Human putative tumor suppressor (LUCA15) mRNA, complete cds Human putative tumor suppressor (LUCA15) mRNA, complete cds U24152 Human p21-activated protein kinase (Pak1) gene, complete cds Human protein kinase PAK1 mRNA, complete cds U25789 Human ribosomal protein L21 mRNA, complete cds Ribosomal protein L21 U27699 Human pephBGT-1 betaine-GABA transporter mRNA, complete cds SODIUM-AND CHLORIDE-DEPENDENT BETAINE TRANSPORTER U31202 Human noggin (NOGGIN) gene, complete cds, (NOG) U32169 Human pro-a2 chain of collagen type XI (COL11A2) gene, complete cds U32907 Human p37NB mRNA, complete cds Human p37NB mRNA, complete cds U33822 Human tax1-binding protein TXBP181 mRNA, complete cds Human tax1-binding protein TXBP181 mRNA, complete cds U37012 Human cleavage and polyadenylation specificity factor mRNA, complete cds Human cleavage and polyadenylation specificity factor mRNA, complete cds U38864 Human zinc-finger protein C2H2-150 mRNA, complete cds Human zinc-finger protein C2H2-150 mRNA, complete cds U40373 Human cell surface glycoprotein CD44 mRNA, complete cds U41517 Human channel-like integral membrane protein (AQP-1) mRNA, clone AQP-1- AQUAPORIN-CHIP 1656, complete cds U43148 Human patched homolog (PTC) mRNA, complete cds U43747 Human frataxin (FRDA) mRNA, complete cds Friedreich ataxia U43842 Homo sapiens bone morphogenetic protein-4 (hBMP-4) gene, complete cds Bone morphogenetic protein 4 U45975 Human phosphatidylinositol (4,5)bisphosphate 5-phosphatase homolog mRNA, Human phosphatidylinositol partial cds (4,5)bisphosphate 5- phosphatase homolog mRNA, partial cds U53204 Human plectin (PLEC1) mRNA, complete cds Human plectin (PLEC1) mRNA, complete cds U53347 Human neutral amino acid transporter B mRNA, complete cds Human neutral amino acid transporter B mRNA, complete cds U59289 Human H-cadherin mRNA, complete cds U59423 Human Smad1 mRNA, complete cds U63717 Homo sapiens osteoclast stimulating factor mRNA, complete cds Human osteoclast stimulating factor mRNA, complete cds U68723 Human checkpoint suppressor 1 mRNA, complete cds U70312 Homo sapiens integrin binding protein Del-1 (Del1) mRNA, complete cds U72245 Human phospholemman chloride channel mRNA, complete cds Human phospholemman chloride channel mRNA, complete cds U75283 Human sigma receptor mRNA, complete cds Human sigma receptor mRNA, complete cds U76992 Human Tat-SF1 mRNA, complete cds Human Tat-SF1 mRNA, complete cds U80998 Human basic helix-loop-helix DNA binding protein (TWIST) gene, complete cds U83460 Human high-affinity copper uptake protein (hCTR1) mRNA, complete cds Human high-affinity copper uptake protein (hCTR1) mRNA, complete cds U90547 Human Ro/SSA ribonucleoprotein homolog (RoRet) mRNA, complete cds Human Ro/SSA ribonucleoprotein homolog (RoRet) mRNA, complete cds U92268 Homo sapiens mitogen activated protein kinase p38-2 mRNA, complete cds U93181 Homo sapiens nuclear dual-specificity phosphatase (SBF1) mRNA, partial cds Homo sapiens nuclear dual-specificity phosphatase (SBF1) mRNA, partial cds X00129 Human mRNA for retinol binding protein (RBP) X00588 Human mRNA for precursor of epidermal growth factor receptor X02910 Human gene for tumor necrosis factor (TNF-alpha) X03742 Human gene for L apoferritin exons 1 and 2 X04412 Human mRNA for plasma gelsolin GELSOLIN PRECURSOR, PLASMA X06614 Human mRNA for receptor of retinoic acid Human mRNA for receptor of retinoic acid X12794 Human v-erbA related ear-2 gene Human v-erbA related ear-2 gene X14420 Human mRNA for pro-alpha-1 type 3 collagen X51801 Human OP-1 mRNA for osteogenic protein X54412 Human mRNA for alpha1(IX) collagen (long form) X55654 Homo sapiens mitochondrial coxII mRNA for cytochrome C oxidase II subunit X55764 Human mRNA for cytochrome P-450 (11 Beta) Cytochrome P450 11 beta X58399 Human L2-9 transcript of unrearranged immunoglobulin V(H)5 pseudogene Human L2-9 transcript of unrearranged immunoglobulin V(H)5 pseudogene X58957 H. sapiens atk mRNA for agammaglobulinaemia tyrosine kinase Agammaglobulinaemia protein-tyrosine kinase atk X60188 Human ERK1 mRNA for protein serine/threonine kinase X60382 H. sapiens COL10A1 gene for collagen (alpha-1 type X) X67337 H. sapiens HPBRII-4 mRNA H. sapiens HPBRII-4 mRNA X70683 H. sapiens mRNA for SOX-4 protein X71661 H. sapiens ERGIC-53 mRNA ERGIC-53 PROTEIN PRECURSOR X74795 H. sapiens P1-Cdc46 mRNA CDC46 HOMOLOG X76770 H. sapiens PAP mRNA H. sapiens PAP mRNA X78712 H. sapiens mRNA for glycerol kinase testis specific 2 Glycerol kinase 2 (testis specific) X87237 H. sapiens mRNA for processing a-glucosidase I H. sapiens mRNA for processing a-glucosidase I X87342 H. sapiens mRNA for human giant larvae homolog H. sapiens mRNA for human giant larvae homolog X92475 H. sapiens mRNA for ITBA1 protein H. sapiens mRNA for ITBA1 protein X94216 H. sapiens mRNA for VEGF-C protein XM_001306 Homo sapiens solute carrier family 16 (monocarboxylic acid transporters), Solute carrier family 16 (monocarboxylic member 1 (SLC16A1), mRNA acid transporters), member 1 XM_001316 Homo sapiens adenosine monophosphate deaminase 1 (isoform M) (AMPD1), Adenosine monophosphate mRNA deaminase 1 (isoform M) XM_001324 Homo sapiens calponin 3, acidic (CNN3), mRNA Calponin 3, acidic XM_001782 Homo sapiens fibromodulin (FMOD), mRNA XM_001826 Homo sapiens alkaline phosphatase, liver/bone/kidney (ALPL), mRNA Alkaline phosphatase, liver/bone/kidney XM_002321 Homo sapiens glypican 1 (GPC1), mRNA Glypican 1 XM_003059 Homo sapiens peroxisome proliferative activated receptor, gamma (PPARG), mRNA XM_003222 Homo sapiens catenin (cadherin-associated protein), beta 1 (88 kD) (CTNNB1), mRNA XM_003730 Homo sapiens cytochrome c oxidase subunit VIIc (COX7C), mRNA Cytochrome c oxidase VIIc subunit XM_003752 Homo sapiens interleukin 3 (colony-stimulating factor, multiple) (IL3), mRNA XM_003913 Homo sapiens integrin, alpha 2 (CD49B, alpha 2 subunit of VLA-2 receptor) (ITGA2), mRNA XM_004063 Homo sapiens early growth response 1 (EGR1), mRNA XM_006121 Homo sapiens cathepsin D (lysosomal aspartyl protease) (CTSD), mRNA XM_009336 Homo sapiens cartilage oligomeric matrix protein (pseudoachondroplasia, epiphyseal dysplasia 1, multiple) (COMP), mRNA XM_009915 Homo sapiens leukemia inhibitory factor (cholinergic differentiation factor) (LIF), mRNA XM_010702 Homo sapiens cathepsin K (pycnodysostosis) (CTSK), mRNA XM_012503 Homo sapiens matrix metalloproteinase 2 (gelatinase A, 72 kD gelatinase, 72 kD type IV collagenase) (MMP2), mRNA XM_012651 Homo sapiens collagen, type I, alpha 1 (COL1A1), mRNA XM_015434 Homo sapiens chitinase 3-like 1 (cartilage glycoprotein-39) (CHI3L1), mRNA XM_016181 Homo sapiens wingless-type MMTV integration site family, member 5A (WNT5A), mRNA XM_017096 Homo sapiens active BCR-related gene (ABR), mRNA XM_017384 Homo sapiens matrix metalloproteinase 7 (matrilysin, uterine) (MMP7), mRNA Matrix metalloproteinase 7 (matrilysin, uterine) XM_017591 Homo sapiens annexin A6 (ANXA6), mRNA Annexin VI (p68) XM_028204 Homo sapiens nuclear factor of kappa light polypeptide gene enhancer in B-cells 1 (p105) (NFKB1), mRNA XM_028642 Homo sapiens integrin, alpha 5 (fibronectin receptor, alpha polypeptide) (ITGA5), mRNA XM_029245 Homo sapiens collagen, type I, alpha 2 (COL1A2), mRNA Collagen, type I, alpha-2 XM_029796 Homo sapiens frizzled-related protein (FRZB), mRNA XM_031221 Homo sapiens interleukin 1, alpha (IL1A), mRNA XM_031288 Homo sapiens aggrecan 1 (chondroitin sulfate proteoglycan 1, large aggregating proteoglycan, antigen identified by monoclonal antibody A0122) (AGC1), mRNA XM_031289 Homo sapiens interleukin 8 (IL8), mRNA XM_032902 Homo sapiens integrin, alpha 1 (ITGA1), mRNA XM_033470 Homo sapiens defender against cell death 1 (DAD1), mRNA DEFENDER AGAINST CELL DEATH 1 XM_033657 Homo sapiens heparan sulfate proteoglycan 2 (perlecan) (HSPG2), mRNA XM_033878 Homo sapiens tissue inhibitor of metalloproteinase 1 (erythroid potentiating activity, collagenase inhibitor) (TIMP1), mRNA XM_034023 Homo sapiens regulator of G-protein signalling 4 (RGS4), mRNA Human RGP4 mRNA, complete cds XM_034556 Homo sapiens chloride channel 7 (CLCN7), mRNA XM_034845 Homo sapiens phosphatase and tensin homolog (mutated in multiple advanced Phosphatase and tensin homolog cancers 1) (PTEN), mRNA (mutated in multiple advanced cancers 1) XM_034890 Homo sapiens fibrillin 1 (Marfan syndrome) (FBN1), mRNA XM_035662 Homo sapiens cathepsin B (CTSB), mRNA XM_035842 Homo sapiens small inducible cytokine A5 (RANTES) (SCYA5), mRNA Small inducible cytokine A5 (RANTES) XM_036107 Homo sapiens integrin, beta 2 (antigen CD18 (p95), lymphocyte function-associated antigen 1; macrophage antigen 1 (mac-1) beta subunit) (ITGB2), mRNA XM_036175 Homo sapiens collagen, type XVIII, alpha 1 (COL18A1), mRNA Collagen, type XVIII, alpha 1 XM_037087 Homo sapiens ATP binding protein associated with cell differentiation Homo sapiens mRNA for ATP binding (APACD), mRNA protein, complete cds XM_037646 Homo sapiens msh homeo box homolog 2 (Drosophila) (MSX2), mRNA XM_037965 Homo sapiens chondroadherin (CHAD), mRNA XM_038584 Homo sapiens tissue inhibitor of metalloproteinase 3 (Sorsby fundus dystrophy, pseudoinflammatory) (TIMP3), mRNA XM_039094 Homo sapiens SRY (sex determining region Y)-box 9 (campomelic dysplasia, autosomal sex-reversal) (SOX9), mRNA XM_040037 Homo sapiens adrenergic, beta, receptor kinase 1 (ADRBK1), mRNA Adrenergic, beta, receptor kinase 1 XM_040385 Homo sapiens S-adenosylmethionine decarboxylase 1 (AMD1), mRNA S-adenosylmethionine decarboxylase 1 XM_042153 Homo sapiens biglycan (BGN), mRNA Biglycan XM_042664 Homo sapiens nuclear autoantigenic sperm protein (histone-binding) (NASP), Nuclear autoantigenic sperm mRNA protein (histone-binding) XM_044120 Homo sapiens fibroblast growth factor receptor 3 (achondroplasia, thanatophoric dwarfism) (FGFR3), mRNA XM_045089 Homo sapiens ATPase, Cu++ transporting, beta polypeptide (Wilson disease) ATPase, Cu++ transporting, (ATP7B), mRNA beta polypeptide (Wilson disease) XM_045802 Homo sapiens paxillin (PXN), Mrna XM_045890 Homo sapiens ADP-ribosylation factor 4-like (ARF4L), mRNA ADP-ribosylation factor 4-like XM_045925 Homo sapiens decorin (DCN), mRNA Decorin XM_045926 Homo sapiens lumican (LUM), mRNA XM_046035 Homo sapiens integrin, alpha L (antigen CD11A (p180), lymphocyte function- Integrin, alpha L (antigen associated antigen 1; alpha polypeptide) (ITGAL), mRNA CD11A (p180), lymphocyte function-associated antigen 1; alpha polypeptide) XM_046758 Homo sapiens tensin (TNS), mRNA XM_046765 Homo sapiens thymidylate synthetase (TYMS), mRNA Thymidylate synthase XM_047231 Homo sapiens fibulin 1 (FBLN1), mRNA XM_047719 Homo sapiens transcription factor 7 (T-cell specific, HMG-box) (TCF7), mRNA Transcription factor 7 (T-cell specific) XM_047802 Homo sapiens a disintegrin-like and metalloprotease (reprolysin type) with thrombospondin type 1 motif, 5 (aggrecanase-2) (ADAMTS5), mRNA XM_048167 Homo sapiens troponin T1, skeletal, slow (TNNT1), mRNA Troponin T1, skeletal, slow XM_048201 Homo sapiens metallothionein 1L (MT1L), mRNA Metallothionein 1L XM_049177 Homo sapiens vascular endothelial growth factor B (VEGFB), mRNA XM_049518 Homo sapiens intercellular adhesion molecule 1 (CD54), human rhinovirus Intercellular adhesion molecule receptor (ICAM1), mRNA receptor 1 (CD54), human rhinovirus XM_049534 Homo sapiens amylase, alpha 2A; pancreatic (AMY2A), mRNA Amylase, alpha 2A; pancreatic XM_049690 Homo sapiens coatomer protein complex, subunit alpha (COPA), mRNA Human coatomer protein (HEPCOP) mRNA, complete cds XM_049864 Homo sapiens colony stimulating factor 3 (granulocyte) (CSF3), mRNA XM_049937 Homo sapiens insulin-like growth factor binding protein 4 (IGFBP4), mRNA XM_050846 Homo sapiens Indian hedgehog homolog (Drosophila) (IHH), mRNA XM_053809 Homo sapiens similar to chondroitin sulfate proteoglycan 2(versican) (H. sapiens) (LOC153633), mRNA XM_054566 Homo sapiens collagen, type VI, alpha 1 (COL6A1), mRNA XM_054686 Homo sapiens caspase 3, apoptosis-related cysteine protease (CASP3), mRNA XM_055254 Homo sapiens fibronectin 1 (FN1), mRNA XM_058069 Homo sapiens matrix metalloproteinase 12 (macrophage elastase) (MMP12), mRNA XM_084239 Homo sapiens retinoic acid receptor responder (tazarotene induced) 2 Human tazarotene-induced (RARRES2), Mrna gene 2 (TIG2) mRNA, complete cds XM_084263 Homo sapiens cytochrome c oxidase subunit VIc (COX6C), mRNA Human mRNA for cytochrome c oxidase subunit VIc XM_084285 Homo sapiens integral membrane protein 2A (ITM2A), mRNA XM_085705 Homo sapiens tissue inhibitor of metalloproteinase 2 (TIMP2), mRNA XM_086368 Homo sapiens MUF1 protein (MUF1), mRNA H. sapiens mRNA for MUF1 protein XM_096277 Homo sapiens collagen, type V, alpha 1 (COL5A1), mRNA Y00985 Human mRNA for manganese-containing superoxide dismutase Y07566 H. sapiens mRNA for RIT protein H. sapiens mRNA for RIT protein Y07570 H. sapiens mRNA for PHAPI2b protein H. sapiens mRNA for PHAPI2b protein Y08999 H. sapiens mRNA for Sop2p-like protein H. sapiens mRNA for Sop2p-like protein Y12692 Homo sapiens mRNA for WNT11 gene Y13936 Homo sapiens mRNA for protein phosphatase 2C gamma Homo sapiens mRNA for protein phosphatase 2C gamma Y15227 Homo sapiens mRNA for leukemia associated gene 1 Homo sapiens mRNA for leukemia associated gene 1 Z22865 H. sapiens dermatopontin mRNA, complete CDS Z50781 H. sapiens mRNA for leucine zipper protein Z50853 H. sapiens mRNA for CLPP H. sapiens mRNA for CLPP

The current invention also encompasses the process of down compression of previously determined 467 genes to a lower number that is still able to characterize the desired number of different cellular status. At present, for the determination of 7 different cell types or development stages, a minimum of 26 spots of different marker genes are preferred, much preferred about 200 such spots. For full information, at least one spot for each of the presently 467 genes (markers) is preferred. A reduction of spot number can be of relevance e.g. if under certain conditions only a small subset of those genes listed in Tab II is required for analysis e.g. in clinical applications. This down compression can be achieved by determining the ratio of actual to target number of genes and then choosing from each cluster accordingly to the determined ratio the necessary number of genes to fulfill the requirement. This process requires to group the number of genes for each analysis of e.g. Tab. I into representative cluster familys from where representative genes can be selected. Such clusters familys can be determined as shown in FIG. 1, namely by grouping clusters together that show a similar expression pattern. For each cluster family a representative number of genes may be choosen according to the compression factor that has been defined. It can easily be seen that for larger clusters like e.g. “A” in Tab I more genes are available to select while in other clusters like e.g. “E” in Tab I less are present. At the end of the process one needs to balance the procedure in order to preserve the characteristics of the expression profile. In order to do so the amount of genes for each analysis should at least be greater than 2 sequences or spots, respectively, of different genes and for the total array at least 30. In order to control such a process classical hierarchical clustering (Stanford) analysis can be performed and checked on graphical presentations like treeview (Stanford). Cluster analysis may group similar expression profiles in families and will allow distinguishing between different cell sources and allows classification of these cell cultures (see FIG. 2). If the cell sources are not properly represented in the cluster analysis it means that the selected marker genes are not balanced.

Example of an Cartilage Specific Micro Array Structure:

To produce a microarray with printed oligonucleotides sequences of approx. at least 10 mers, preferably at least 25 mers, some sequences of table II need to be further processed. Since some of the determined sequences in Tab II are only expressed sequence tags (herein referred to as EST), they do not correspond to or represent the full-length cDNA. Therefore the EST preferably is BLAST searched with the public database at NCBI and the corresponding full-length cDNA determined. Only by having the correct and full-length cDNA it is possible to design oligomeric sequences that are balanced to each other and minimize any cross reactivity. Exemplary polynucleotide sequences (targets) are provided in the sequence listing of Table III. The cartilage related polynucleotide sequences as e.g. listed in Table III and other polynucleotide sequences known as key cartilage genes from the literature can be immobilized on a substrate and used as hybridizable array elements in a microarray format. Such microarrays can be composed of a subset of oligonucleotides representing e.g. sequences listed on Tab. II but modified to represent only full-length cDNA sequences. The used polynucleotides for the production of such a microarray can either be 50mer or also PCR (polymerase chain reaction) products but at least need to be longer then 10 bases. It should be noted that for microarray production also PCR products from the corresponding determined sequences directly or the full length cDNA can be used and it is not restricted just to oligonucleotides.

Methods to anchor such oligonucleotides or polynucleotides on a solid support are described in literature, together with information on length dependent distances between each oligo or polynucleotides and spots. (see e.g. Principal and Practice, DNA microarrays: gene expression analysis B. Jordan, Springer, 2001)

When polynucleotides are employed as hybridizable array elements in a microarray and depending on the software used, the array elements may be organized in an ordered fashion so that each element is present at a specified location on the substrate. If the array elements are at specified locations on the substrate, the hybridization patterns and intensities (which together create a unique expression profile) can be interpreted in terms of expression levels of particular genes. This expression profile can then be used and may be correlated with any effect associated with a tissue and/or compound or to be investigated with regard to a specific tissue and/or compound and allows comparison with already existing data.

One of such useful application of using ordered polynucleotides on microarrays is e.g. the comparison of gene expression profiles from a new sample e.g. a tissue biopsy, with already determined characteristic gene expression profiles that are preferably stored in a database. Such stored gene expression profiles are e.g. of major importance if microarrays are applied in the clinic. In this case advantageously a database is set up that stores the corresponding gene expression profiles and advantageously also all patient informations, e.g. history, blood pressure etc. By including all patient data and gene expression profiles in the analysis process and then starting a comparison with an expression profile from a new biopsy, it becomes possible to achieve a stronger correlation with the clinical outcome. This will allow to determine which therapy shall be applied, or even to modify an existing therapy, e.g. to add growth factor x at a concentration y during the ex vivo tissue engineering phase. It may also be the case that the biopsy sample will demonstrate a poor gene expression profile that precludes the successful application of a modern therapeutic cell/tissue approach. Such cases would then only qualify for traditional surgical approaches, and hence would not obtain the benefits of the tissue engineering process.

In analogy, the assessment of in vitro produced cartilage can also be performed. In the same way as mentioned above cell culture parameters, like e.g. culture media conditions, growth factor concentration, are preferably stored in a data base together with the corresponding gene expression profiles. Comparison of the database entry with new profiles of new samples can then be used to assess the quality of the new in vitro produced tissue.

Subject Arrays and Their Use:

It should be noted that the invention described here is not dependent on any special array format rather than the possibility to select from an extended list of 467 novel key cartilage genes as well as meaningful gene expression patterns. A presently preferred subject array is a novel cartilage specific microarray that includes 187 genes that in the scope of this invention have been determined to be cartilage related and 140 genes that have been connected to cartilage in literature (see also Tab II). Normally, in high-density array procedures up to 10000 genes are usually applied and are not specific for certain applications. As one major general drawback, this results in massive data overflow and impaired data analysis due to difficult data handling and procedures. A preferred array has in its current state a minimal number of 150 genes, presently much preferred at most 333 genes, all of those with demonstrated relevance within cartilage tissue. Another major limitation has become apparent. While the invention WO01/24833 A2 describes a few marker genes associated with cartilage phenotype stability they do not allo w to extensively describe chondrocyte cultures in details. No comprehensive classification of the different cell populations and culture conditions is possible as well as no gene expression profile or fingerprint can be achieved. Gene expression profiles determined with a set of genes represented in Tab II may allow to perform a more comprehensive analysis of different cell cultures conditions. Furthermore it may allow to compare and classify different tissue or the result of the different applied cell culture conditions. The above mentioned topics may only be possible with the disclosed invention as outlined within the following applications.

The inventive array CART-CHIP 300 ™ may be applied to classify (quality control) any source material, such as human cartilage biopsies, mesenchymal stem cell containing bone marrow aspirate, or pre-chondrogenic cells containing tissue according to pre-defined categories with respect to their capacity to re-build or re-organize a hyaline cartilage-like matrix in vitro. A rough subdivision could be for example “A”, “B”, or “C”. While “A” will easily produce cartilage-like matrix, “B” will require special treatment to achieve an implantable construct, and “C” will represent those cases that do yet not qualify for such a procedure. This biopsy classification system will allow:

-   -   Quality control of the starting biopsy material and therefore         optimization of the downstream process regarding e.g. in vitro         tissue engineering applications     -   Diagnostic evaluation of the patient and candidate treatment         methods (e.g. CARTIGRAF™) to ensure a cost-optimized procedure     -   Quality control of in vitro tissue engineered products

The subject array of the present invention can be employed for all kind of research and developmental studies related to in vitro tissue engineering of cartilage. The possibility to assess proliferation, differentiation or re-differentiation as well as de novo matrix formation processes through analyses and comparison of a plurality of key cartilage genes (positive/negative markers) within one single experiment replaces current trial and error approaches and is thus far more rational.

The subject array can be applied to screen all kind of drugs, e.g. hormones, growth factors, within in vitro chondrocyte cultures regarding a potential beneficial effect on proliferation, differentiation, de novo matrix formation. The deduced expression profiles can then be compared with existing data of e.g. native cartilage tissue and used to further optimize the process. Additionally the expression profiles can be compared with data from human adult and human infant cartilage to deduce a pathway or a strategy of how to induce more tissue formation in vitro.

The subject array of the preferred embodiment is very well suitable to better understand reaction pathways leading to new responses of chondrocytes in vitro. Only key cartilage genes comprising the whole spectrum of functional gene categories are to be investigated. This can be used to study the complexity of degenerative cartilage process in vitro and the respective influence of potential beneficial drugs.

The subject array may be used to optimize cultures for in vitro cartilage formation starting from human cell sources other than cartilage like e.g. mesenchymal stem cells or bon marrow aspirates.

This subject array will be preferably used as powerful alternative for conventional molecular biology tools beside more established histological and biochemical analyses. By focusing on the most prominent cartilage marker genes being either positive or negative, it is possible to characterize cartilage or cartilage related tissues as well as cell cultures thereof. In this respect, the subject array can replace conventional RT-PCR studies performed to check for cartilage marker gene expression, e.g. collagen I versus collagen II, aggrecan versus versican. By applying this subject array the set of markers will be easily increased by simultaneously simplifying the experimental procedure and enhancing the outcome.

The subject arrays of the present invention have several advantages compared to existing microarrays as well as to conventional gene expression tools such as RT-PCR, Northern Blots etc.

Most importantly, the subject arrays are all based on key cartilage genes. Beyond all the key cartilage genes known from the literature (˜100-200 genes), 467 additional cartilage relevant genes have been discovered. Thus a significantly increased pool of cartilage key genes exists to choose from for various applications. For instance, to understand degenerative processes as they occur in OA or RA by study of complex biological reaction pathways, it is important to follow expression of a relatively large number of genes.

EXAMPLES

The examples are described for the purposes of illustration and are not intended to limit the scope of the invention.

Example 1 Analysis of Various Human Cartilage Samples

Useful for characterizing chondrocyte cultures derived from different human cartilage samples (adult and fetal), where adult samples are different with respect to their capacity to form living tissue engineered equivalents under high density culture conditions.

Adult chondrocytes show different gene expression clusters compared to fetal chondrocytes and can be further distinguished from samples that will not produce living cartilage constructs (failures).

Human chondrocytes from adult and fetal articular cartilage were proliferated in DMEM-F12 medium containing 10% FCS over several passages and transferred to pellet cultures (0.5*10⁶ cells) in serum free DMEM-F12 medium supplemented with Ascorbate and Insulin medium. Proliferated cells were directly lyzed with RLT buffer (RNeasy® Mini Kit, Qiagen) after trypsin release from plastic substrate, shredded (QIAshredder, Qiagen) and kept frozen at −80° C. in lysis buffer for later processing. High density pellet cultures were cultivated for 2 weeks if not otherwise specified, subsequently washed with phosphate buffered saline (PBS) and lyzed in RLT Buffer (supplied with RNeasy® Kit). Total RNA was isolated from all samples as described in the manual provided with the RNeasy kit and stored at −80° C.

Fluorescent labeled aRNA (amplified RNA) constructs were obtained by in vitro reverse transcription of the RNA followed by an in vitro amplification reaction.

2 μg of isolated total RNA were used per sample to amplify RNA by applying only one cycle of in vitro transcription (IVT, Millenium Biologix AG, Application Note).

2 μg of total RNA from each sample was primed with oligo(dT)_(24-mer) (containing a T7 RNA Polymerase Promotor) and reverse transcribed using 400 Units SuperScript II reverse transcriptase enzyme, nucleotides, 5× Reaction Buffer and Dithiothreithol (DTT) as described in protocol provided with the enzyme. For ribonuclease protection 1 μL RNase inhibitor (10 Units) was used to prevent RNA degradation during first strand synthesis. This first strand synthesis reaction was incubated for 1 hour at 42° C.

To the first strand synthesis reaction 93 μl nuclease free water, 30 μl second strand buffer (Invitrogen, Basel, Switzerland) and 1.5 μl nuclotide mix (dATP, dTTP, dGTP, dCTP, 25 mM each) was added.

Second strand synthesis reaction mix was obtained by adding 40 Units E. coli polymerase I (New England Biolabs, BioConcept, Allschwil, Switzerland), 10 Units E. coli DNA Ligase (New England Biolabs, BioConcept, Allschwil, Switzerland) and 2.5 Units Ribonuclease H (Fermentas, Labforce AG, Nunningen, Switzerland). Reaction was incubated for 2 hours at 16° C.

After this incubation step remaining RNA was degraded by adding 7.5 μl 1M sodium hydroxid containing 2 mM EDTA (Ethylenediaminetetraacetic acid) for 10 minutes at 65° C. 7.5 μl 1M Hydrochloric acid was added to neutralize the reaction.

The obtained double strand DNA was purified in a QIAquick® PCR purification kit (Qiagen, Hilden, Germany) and concentrated to 7.5 μl. To this concentrated RNA following reagents were added to obtain aRNA synthesis mix: 2 μl ATP (Adenosine triphosphate, 75 mM), 2 μl GTP (Cytidin triphosphate, 75 mM), 2 μl GTP (Guanosin triphosphate, 75 mM), 2 μl UTP (Uridin triphosphate, 75 mM), 1.5 μl 5-(3-aminoallyl)-Uridin triphosphate and 2 μ, reaction buffer and 2 μl Enzyme mix (both provided with Ambion MegaScript Kit, Ambion, Cambridgeshire, United Kingdom).

This aRNA synthesis mix was incubated for 4 hours at 37° C. Remaining double strand DNA was digested by adding 1 μl Dnase I for 15 min at 37° C. aRNA was cleaned and concentrated with an RNeasy® Mini Kit column (Qiagen, Hilden Germany) and then concentrated to a final volume of 9 μl.

Fluorescent dye molecules were coupled to the reactive aminoallyl groups of the incorporated a 5-(3-aminoallyl)-Uridin triphosphate molecules. One aliquot of either Cy3™- or Cy5™-mono reactive dye (Amersham Biosciences, Buckinghamshire, United Kingdom) was diluted in 40 μl water free Dimethyl sulfonoxide. 10 μl, of one of the diluted Cy™ mono reactive dyes was added to each sample buffered in 100 mM Carbonate buffer (pH 9.00). Reaction was quenched after 1 hour by adding 10.4 μl Ethanol amine for 15 min at room temperature.

Unincorporated dye molecules were removed by ethanol precipitation. 2 μl Glycogen (Invitrogen, Basel, Switzerland) was added as carrier during precipitation. After precipitation aRNA pellet was washed with 80% ethanol, dried and resuspended in 50 μl 1× Fragmentation buffer (200 mM Tris(hydroxymethyl)aminomethane hydrochloride, 500 mM Potassium acetate, 150 mM Magnesium acetate). aRNA was fragmented for 35 min at 94° C. and placed on ice immediately. Fragmented aRNA was dissolved in 900 μl hybridization buffer.

For denaturation aRNA was incubated for 5 min at 98° C. and centrifuged for 30 sec at full speed in a microcentrifuge.

One CART-CHIP™ 300 (Millenium Biologix AG, Switzerland) was placed face down in a standard hybridization chamber. Hybridization solution containing the denatured and labeled aRNA sample was injected using a standard micropipet whereas Cy3™ and Cy5™ samples were hybridized together in one hybridization chamber (Millenium Biologix AG, Switzerland). The microarrays were incubated overnight at 42° C. in a PCR thermal cycler (TGradient, Whatman Biometra GmbH, Göttingen, Germany).

After incubation unspecific aRNA probe was washed away with 1×SSC, 0.1% SDS for 5 min at room temperature, followed by another wash step in 1×SSC, 0.1% SDS for 5 min and rinsed with 1×SSC without SDS for 1 minute to remove excessive SDS. 1×SSC was discarded. Remaining 1×SSC buffer on the slide surface was removed by centrifuge the slide for 2 min at 1500×g.

The dried CART-CHIP™ 300 were then scanned using an Affymetrix 418 microarray scanner.

Expression level raw data for every spot was obtained with ImageQuaNT (Molecular Dynamics). Raw data was normalized by dividing every expression value by total expression value of all spots for every sample and filtered by setting all values below the 25 percentile to the value of this 25 percentile to remove noise (25 percentile threshold).

For each sample (e.g. de-differentiated and re-differentiated chondorcytes) a list of all measured genes was generated. This so called gene expression profile was then used for subsequent analyses.

Further data analysis was performed using either hierarchical clustering with cluster.exe (written by Michael Eisen, Stanford University) or Self Organizing Maps (SOM), such as GeneCluster developed by Whitehead Institute (Massachusetts Institute of Technology, MIT). The settings of the software were optimized until a reasonable number of clusters resulted that were able to represent the comparison thoroughly. In the following example the parameters were as following:

Basic parameters: SOM rows 6; SOM col: 4; #epochs=3000; #seeds=1

Advanced parameters: initialization: random vectors; neighborhood: bubble; alpha 1=2; alpha f=0.005; sigma 1=3000; sigma f=2.

FIG. 1 shows a typical result from a SOM analysis with the above mentioned basic parameters, whereas FIG. 2 shows an example of a graphical presentation of a cluster analysis and viewed by the software treeview.

Example 2 Quality Control and Human Cartilage Sample Classification

Useful to demonstrate how CART-CHIP™ 300 can be used to differentiate between diverse cell culture conditions, to distinguish different patients, to study the influence of 3D culture conditions and to serve as a quality control tool during any tissue engineering process.

Human chondrocytes isolated from 4 different donors were proliferated over one passage (P1) and then cultivated as high density pellets (0.5*10⁶ cells) in 3D culture for 7 and 14 days. RNA samples were taken from proliferated as well as from 3D cultured cells resulting in totally 12 different samples as shown in FIG. 8. RNA isolated from this samples was shreddered in a QIAshredder (QIAGEN, Hilden, Germany), amplified, hybridized, washed and scanned as described in Example 1.

Data sets for all 12 samples were extracted and normalized as described in Example 1 to perform cluster and SOM analysis as noted below. Cluster analysis was performed using normalized data computed with GeneCluster.

FIG. 3 shows a picture of such a cluster analysis for all 12 samples (#1-#12) consisting of 20 clusters (c0-c19)

Every cluster represents a typical gene expression pattern for all 12 samples indicated by a point, starting from sample #1 on the left hand side to sample #12 on the right hand side in every cluster. For example cluster c0 represents the expression level of 104 genes in all 12 samples in a given range indicated by the lines located above and below the computed points.

Another example for gene expression levels that behave similar for different culture conditions and donors are depicted in clusters c3, c4, c9 and c10. Meaning that every subset of the three donor specific points #143, #4-#6, #7-#9, #10-#12 (see Tab V for detailed description) have gene clusters that behave similar in all analyzed samples.

An example of differently behaving genes is indicated in cluster c13, representing 10 genes that behave similar in donor #1 and #2 but show a different gene expression patterns for donors #3 and #4.

More detailed analyses are shown in FIG. 4, FIG. 5, and FIG. 6. The clusters produced in these figures clearly demonstrate differences as well as similarities in cell behavior for either t0, t7 or t14 days, respectively.

Another software algorithm that can be applied for analysis of large amounts of data coming from gene microarrays is called hierarchical cluster analysis, whereas genes and/or different conditions with similar behavior in gene expression are clustered together. All hierarchical cluster analyses were performed using Cluster software described in Eisen et al. (1998) PNAS 95:14863) and displayed using treeview.exe developed by same author.

FIG. 7 shows such a cluster of selected genes for all 12 samples analyzed. Every square is representing one single gene expression value. Different intensity means different expression levels. Dark squares are representing samples without any significant change in gene expression compare to the other samples or patients. Bright squares are indicating samples in which genes are up- or down-regulated relative to other samples analyzed. A so called cluster of genes is a group of genes that behave similar from one donor to the other donors.

Not only genes but also samples can be clustered together. These clusters are called similarity dendrograms, shown in the top part of FIG. 7. These tree-like structures illustrates similarities in gene expression between different samples or donors. The closer a sample (#1 . . . #12) is located to another sample in this dendrogram the more similar gene pattern they have.

Interestingly to see is that the seven samples located at the right side of the dendrogram (samples #1, #2, #5, #7, #8, #10 and #11) are clustered together. This samples are representing t0 and t7 conditions as described above (illustrated in Tab V), whereas a cluster of 4 samples in the middle of the dendrogram (samples #3, #6, #9 and #12) are representing only t14 samples. This means a microarray of the current invention is able to distinguish between de-differentiated, proliferated samples (t0 and t7) and re-differentiated samples in a later stage (t14).

An outlier represents sample #4 located at the most left side of FIG. 7. which represents proliferated chondrocytes (t0) from donor 2 and could not clustered together with the remaining proliferated samples. Interestingly, this sample that it is not similar to all other proliferated samples (#1, #7 and #10) was impaired with its capacity to form cartilage tissue equivalents following expandation in 2D culture. The biochemical analysis revealed a lower amount of total collagen/DNA for this sample and immunohistochemisty with collagen II antibodies resulted in only weak staining for a collagen II.

Example 3 Aortic Fibroblasts vs. Chondrocytes

Example to differentiate between expanded chondrocytes and aortic fibroblasts cultivated over 14 days in 3D settings.

A human aortic fibroblast cell source was proliferated and brought to 3D culture. RNA was isolated after 14 days of culture. Expression data analysis was performed as described in previous Examples 1 and 2 using CART-CHIP™ 300 microarray.

A hierarchical cluster analysis was performed as described in example 2. Samples representing 3D culture after 14 days (t14) were included in said data analysis (samples #3, # 6, # 9 and #12, see Tab V).

The result of the described analysis can be seen in FIG. 8. The upper part of the figure shows a dendrogram as described in example 2. Aortic fibroblasts are not clustered together with human chondrocytes. The cluster shows a significantly different pattern compared to all other cultures.

Obviously a gene expression pattern of an aortic fibroblast cell source can be clearly separated from a gene expression pattern of human chondrocytes. A micorarray of the present invention is therefore not only able to study differences between different chondrocyte culture conditions but also to distinguish between cells isolated from different tissues.

Example 4 Arthritic Conditions vs. Healthy Conditions

Useful to distinguish between normal healthy chondrocyte behavior from cells resembling an arthritic phenotype. Interleukin-1β is known to play a central role in the inflammation and connective tissue destruction observed in both rheumatoid arthritis (RA) and osteoarthitis (OA). Stimulation of in vitro chondrocyte cultures with Interleukin-1β thus represents a simple experimental arthritis model.

The chondrocyte cell source from donor 4 (see Tab V) was proliferated over 3 passages and then cultivated as high-density pellet cultures (0.5*10⁶ cells) for 16 hours and 7 days either in the absence or presence of Interleukin-1β (30 ng/mL). RNA was isolated from all samples, hybridized to CART-CHIP™ 300 and expression profiles were generated as described in Example 1.

A hierarchical cluster analysis was performed as described in Example 1 and the dendrogram and a selection of the representative gene clusters are shown in FIG. 9. This clearly shows that already a short stimulus of Interleukin-1β results in alteration of the chondrocyte phenotype with gene expression changes that can be distinguished from untreated normal chondrocyte cultures.

Appendix TABLE I Number of marker Experiment and correlated gene genes for each experiment expression analysis experiment (analysis) (analysis) 2D marker adult vs. fetal/infant 151 A 2D/3D adult vs. fetal/infant 96 B 3D marker failure 165 C 3D marker adult/fetal/infant 350 D 2D/3D marker adult 48 E Time dependent failure marker 75 F 3D failure marker 41 G Apoptosis related failure markers 30 H

TABLE V Sample Numbers (#) Proliferation 7 days in 3D culture 14 days in 3D culture (t0) (t7) (t14) Donor 1 #1 #2 #3 Donor 2 #4 #5 #6 Donor 3 #7 #8 #9 Donor 4  #10  #11  #12

Table IV shows the results of a bioinformatic analysis of gene expression profiles of the 467 cartilage specific marker genes. Clus- Accesion ter SOM Description H4 P2 3D failure pool H5 P1 2D H4 P2 2D H4 P1 2D H5 P1 3D AA283693 2 2D/3D 0.620146952 0.563012608 0.543651567 0.467462855 0.502962907 0.971864748 AA845156 2 2D/3D 1.822887384 1.974062517 1.793508407 2.056234156 2.134502741 2.109619189 R52548 22 2D/3D 42.15305285 24.91632836 36.03204148 38.20234471 38.12886555 36.73272848 T67128 4 2D/3D 0.114907897 0.165223543 0.175143838 0.230515232 0.111518632 0.115949318 AA845015 8 2D/3D 5.152985898 5.163366386 4.600617698 5.490400618 5.613170246 5.081143315 AA937895 8 2D/3D 2.841572293 2.035680155 2.574530008 3.532376413 2.904240444 2.88987266 AA844998 15 2D/3D 9.597114182 13.63928438 14.05976269 12.99542024 10.56590581 11.73420854 AA844518 16 2D/3D 34.95251239 32.56636092 35.29612046 39.31305252 38.10953207 32.87879549 AA894557 16 2D/3D 56.23673424 43.61031652 36.30704958 58.47875881 59.70042623 48.33981986 AA872001 20 2D/3D 81.81389212 56.44454367 38.30704958 89.11888026 82.12028621 54.71499842 H09590 1 2D/3D 0.538758103 0.606028834 0.923090371 0.610970303 0.582446119 0.488768664 AA888278 11 2D/3D failure vs. 0.872435407 1.541743481 1.320841185 1.418331235 1.44054309 1.142574932 cartilage AA490855 11 2D/3D failure vs. 5.256355042 3.982907846 3.740473099 5.019900855 5.072810576 4.193769533 cartilage H05820 2 2D/3D failure vs. 0.326771454 0.298568027 0.723972051 0.373421152 0.291228161 0.42426813 cartilage N57766 3 2D/3D failure vs. 1.244580679 1.430645893 1.237128762 1.435760892 1.621084111 1.793426963 cartilage AA873885 3 2D/3D failure vs. 2.389977721 1.402865274 1.960300849 2.6421261823 1.174416144 2.132327967 cartilage AA878880 3 2D/3D failure vs. 1.975516413 0.706271534 2.235200516 2.852909562 2.341957596 2.325462095 cartilage R54818 6 2D/3D failure vs. 1.433222617 1.408764041 1.026467036 1.653245959 1.555280568 1.313068482 cartilage AA458830 23 2D/3D failure vs. 6.225911646 7.131102869 6.449691069 7.181223742 7.435528281 8.273231774 cartilage W37884 11 2D/3D failure vs. 3.42542852 3.434948923 2.822843216 3.920408386 4.031440051 2.924316539 cartilage N63192 11 2D/3D failure vs. 2.016416698 1.880341817 1.955128455 2.604284112 2.555986174 1.868963757 cartilage R55789 11 2D/3D failure vs. 3.050734207 2.916359387 2.459270284 3.086180697 2.768681643 2.87080332 cartilage R56871 14 2D/3D failure vs. 8.05304356 6.763218112 9.202602512 9.315742803 9.656817425 6.703182113 cartilage AA448659 15 2D/3D failure vs. 4.086696472 7.404785733 3.70432959 4.624265635 4.780951569 6.12097414 cartilage AA235388 11 2D/3D failure vs. 4.793907209 5.590616298 6.430749719 6.119406496 5.787215762 5.448903875 cartilage W37769 18 2D/3D failure (adult) 9.666153573 9.041797201 10.48060069 9.18235887 9.779057041 9.301866835 AA421701 18 2D/3D failure (adult) 6.39851543 6.944977864 6.787000717 7.805796465 8.044148563 6.091762141 NB1029 22 2D/3D failure (adult) 11.25612666 7.536201205 9.791822816 10.26909779 11.09189885 11.24056884 AA644128 22 2D/3D failure (adult) 8.87008786 8.634238881 8.980680688 10.62210945 11.07634385 8.151499526 N26536 23 2D/3D failure (adult) 1.127588919 0.934050212 1.276862277 1.339090617 1.722862887 1.543708239 AA890663 23 2D/3D failure (adult) 7.502466565 6.586516448 8.707110583 7.582524442 6.272458865 6.92700675 AA405987 17 2D/3D failure (adult) 8.007848934 7.398131991 7.180024565 9.644484085 9.329435489 7.017060375 AA888182 4 2D/3D failure (adult) 1.159709394 0.997393508 1.761866087 1.609558388 3.076463138 1.864862168 H09730 23 2D/3D failure (adult) 6.016598561 4.38097919 4.512218706 5.75467456 5.708409303 4.568792922 AA285155 22 2D/3D failure (adult) 3.911163963 4.375731694 4.103404996 3.976701687 3.566916248 4.846020855 AA873351 1 2D/3D failure (adult) 0.715716774 0.448961688 1.143094938 1.086305702 0.6643881 0.576661574 H12320 1 2D/3D failure (adult) 0.561973556 2.57723008 0.516528265 0.364969035 0.426769958 1.536698149 AA856558 1 2D/3D failure (adult) 2.083875002 0.734906688 0.98056715 1.17363108 0.340692619 1.146139751 R43581 2 2D/3D failure (adult) 2.106534421 0.601495831 2.998509555 1.885349164 1.78560062 1.913887067 AA633768 2 2D/3D failure (adult) 0.641660349 0.394897957 0.989161585 0.80349418 0.676931906 0.471526265 AA496880 2 2D/3D failure (adult) 0.819001028 0.446244605 1.078973938 0.96946743 1.001567705 0.612915544 AA625632 4 2D/3D failure (adult) 1.493144759 0.535655307 2.320048835 2.145585116 1.461514048 1.208574247 R40850 3 2D/3D failure (adult) 0.682308084 0.595008017 1.325881758 1.168113039 0.576613768 0.894548353 AA486072 9 2D/3D failure (adult) 2.033091331 6.009395549 1.397241773 1.306335917 1.667598386 4.321686833 N80129 4 2D/3D failure (adult) 0.351536161 0.860381999 1.012366932 0.336466005 0.442915198 0.530986466 T67270 5 2D/3D failure (adult) 1.963529863 1.201108371 3.314347202 3.108011309 2.159811403 1.603756559 AA776304 6 2D/3D failure (adult) 0.862462885 0.468437574 1.000125084 1.050963409 0.840547206 0.712318096 AA64743 6 2D/3D failure (adult) 1.419135024 0.972417085 1.72467226 1.536612587 1.441826888 1.267977482 AA663983 7 2D/3D failure (adult) 0.992237246 0.562108496 2.11407474 1.505738573 1.504937007 1.363338621 AA634008 8 2D/3D failure (adult) 1.633316095 0.546444823 1.670198138 2.668127971 1.579545189 1.258079751 AA683050 8 2D/3D failure (adult) 1.604349305 0.609305829 2.869733356 2.49429974 1.663928936 1.276592262 AA775874 3 2D/3D failure (adult) 1.787634446 0.639410548 1.3560157 1.263003994 1.234797131 2.355664777 AA029934 19 2D/3D failure (adult) 2.356636943 1.558846586 2.787420472 2.743130089 2.330296295 2.141155369 AA872397 21 3D adult vs. fetal 19.50233862 17.51369555 30.1499536 23.26630505 24.52945535 17.84127943 AA428195 3 3D adult vs. fetal 7.071920614 5.267967863 6.138557001 7.23507727 7.48271081 5.35099208 AA478724 3 3D adult vs. fetal 5.248364716 3.470387154 4.172040349 5.052705318 5.168529149 6.015264941 T40541 2 3D adult vs. fetal 3.238889946 12.31479553 2.521870024 1.484626573 2.463205882 6.610009772 N33214 2 3D adult vs. fetal 2.65473448 2.961197481 1.727113613 1.517196864 1.863643598 5.009412045 W69399 2 3D adult vs. fetal 2.836334543 2.418647835 2.384859773 1.271557098 2.218662035 4.984390107 H85454 2 3D adult vs. fetal 2.580688668 1.88582991 1.388608005 1.244844015 1.534483051 3.983108173 T71284 2 3D adult vs. fetal 1.986879018 2.475258573 0.744183047 0.768307025 0.765085426 4.427870608 N95418 2 3D adult vs. fetal 3.21585913 1.583715156 1.572090076 1.152454683 1.55045145 4.188689886 AA430675 18 3D adult vs. fetal 20.40011187 13.5115773 23.35924913 19.03556124 22.70504494 16.6788312 AA682851 21 3D adult vs. fetal 25.44236224 17.10952218 33.76684841 28.22129217 26.86052023 24.00871315 AA427433 3 3D adult vs. fetal 6.682930727 4.737477088 5.985736157 7.06879228 7.217223212 6.130314027 AA100296 21 3D adult vs. fetal 16.73518464 14.16222538 25.17519653 21.63898477 21.16013508 17.85039728 AA070997 20 3D adult vs. fetal 21.13329064 16.5080222 30.63855114 26.1438582 26.27182686 19.46457951 R27585 20 3D adult vs. fetal 18.95998765 13.51396253 26.82697423 21.45047839 21.44832633 16.96978325 N71628 20 3D adult vs. fetal 18.60838994 16.33393806 26.68120529 21.6113028 21.33877846 16.98487296 AA484566 20 3D adult vs. fetal 16.06992797 10.85633998 18.70563179 17.27026288 17.70073984 14.07448353 AA043228 20 3D adult vs. fetal 12.81312824 9.803849829 17.97620829 14.19332756 14.28559054 10.85546077 AA478273 19 3D adult vs. fetal 52.06929197 32.17017287 36.30704958 47.93432102 43.94005516 45.65265571 H05618 2 3D adult vs. fetal 2.632906988 4.642300363 1.284880525 0.973906438 1.326880261 4.570563698 AA405562 5 3D adult vs. fetal 6.993441389 4.782974749 5.219581264 6.611843236 6.447811984 5.853372531 AA147043 5 3D adult vs. fetal 5.26712976 4.856265473 8.499381882 5.561464269 5.30607401 5.35955551 AA035384 5 3D adult vs. fetal 6.401728539 4.12666021 7.578771481 6.904866564 7.128981272 5.672655498 R60150 5 3D adult vs. fetal 4.215197474 4.38442636 4.860194724 4.973592031 5.301613877 4.146462455 N64051 5 3D adult vs. fetal 5.426681636 4.928078432 5.608870527 5.622962025 5.371210998 4.561721051 AA405748 5 3D adult vs. fetal 5.368605864 3.19002151 4.353339926 4.106442793 5.477050315 4.525369392 AA461110 5 3D adult vs. fetal 3.575328316 2.604624915 4.130714878 3.915938843 4.131312686 3.482794563 AA845167 5 3D adult vs. fetal 3.78578459 3.609211434 4.618092536 4.244750176 4.779380405 3.825719327 AA443118 5 3D adult vs. fetal 4.314381512 6.09876062 6.276759492 5.303887624 5.568448187 5.169715811 N92319 3 3D adult vs. fetal 4.572213322 3.033513374 3.354505947 3.067302105 3.243795499 6.319683552 AA187148 5 3D adult vs. fetal 5.511820527 5.984833947 9.561458451 7.538771775 7.330918349 4.996228711 AA253413 3 3D adult vs. fetal 5.753953945 4.708057923 5.13409191 8.221909098 6.216223439 4.722726065 AA045701 4 3D adult vs. fetal 7.244740869 7.004200569 9.55974171 8.437552392 9.263082719 6.552005827 AA164562 4 3D adult vs. fetal 7.627425507 5.216496788 8.699986728 7.923881699 9.508233607 6.844029007 AA486357 4 3D adult vs. fetal 6.41575883 6.975113261 10.40229719 7.96745072 8.41742583 6.451127762 AA180742 4 3D adult vs. fetal 5.52121367 6.234552553 8.103930847 6.983167569 6.946238241 6.26480073 AA454743 4 3D adult vs. fetal 7.511488312 9.369158012 11.34696747 9.562551962 9.456937824 7.36978659 AA437226 4 3D adult vs. fetal 7.112744497 8.791653264 10.80511143 8.266289799 8.507470188 7.034847567 AA458849 3 3D adult vs. fetal 5.469328544 3.66373147 4.903306694 4.827076947 5.660206542 4.514629804 AA604891 3 3D adult vs. fetal 5.258178068 8.251213126 6.90322093 6.369912634 5.676523521 7.288981598 AA609655 18 3D adult vs. fetal 21.33429032 19.08081783 30.01089002 23.9982204 25.31681248 20.18144049 AA599158 6 3D adult vs. fetal 5.73905777 4.765585417 8.346245119 6.423634441 6.61080494 5.063695516 AA052932 2 3D adult vs. fetal 4.160294487 2.183896002 2.762899749 2.096861401 2.192248117 5.413063915 AA769328 2 3D adult vs. fetal 3.49664111 3.795346147 3.543244396 3.202155462 1.664435653 4.680897198 AA129537 6 3D adult vs. fetal 5.490099148 4.033511964 6.753224678 5.270505052 6.104594281 4.571138177 AA486209 2 3D adult vs. fetal 2.951127838 2.622458107 2.396628552 1.876778497 2.154038566 4.999645899 H39016 2 3D adult vs. fetal 2.815824978 1.826966689 1.671944771 1.253970839 1.643279353 4.632563322 AA464217 2 3D adult vs. fetal 2.270265016 2.131631711 1.520659008 1.064618518 1.329400245 4.21418601 T95053 2 3D adult vs. fetal 2.688707692 5.33382498 1.794683232 1.531765242 1.715814755 5.3630072 AA454640 2 3D adult vs. fetal 2.102886248 1.537570373 1.346779699 1.127849141 1.214174754 4.183264486 AA448400 2 3D adult vs. fetal 3.306242137 2.235006202 1.747624063 0.631226114 1.568082834 8.474436694 H13691 19 3D adult vs. fetal 54.00052945 38.06027395 36.30704958 53.01474929 49.86794621 50.27373427 AA132086 2 3D adult vs. fetal 3.337097743 3.257550359 2.293125381 1.567514408 1.604751828 5.862999872 AA488073 2 3D adult vs. fetal 4.351033023 4.04194944 1.452692862 3.511334664 4.118886207 5.708773871 N40945 2 3D adult vs. fetal 3.447096842 2.154588097 2.501683281 2.52085183 2.297385171 4.762374759 R55705 2 3D adult vs. fetal 2.909308613 1.851341621 1.432688968 1.212749384 1.638105054 4.556458468 H50114 2 3D adult vs. fetal 3.301736569 1.908387922 1.705840938 1.407414465 1.781048668 4.589212608 AA452841 2 3D adult vs. fetal 3.981943611 1.231373773 1.0248198 0.963983432 1.620834153 4.505595396 W73790 2 3D adult vs. fetal 3.914888537 1.713927735 1.679258731 1.608715372 2.253084809 4.790266687 N30302 17 3D adult vs. fetal 16.236426 14.33825503 20.17733457 16.72882972 18.60385984 15.82011639 AA291556 2 3D adult vs. fetal 2.858389118 6.164431067 2.312941111 1.624968319 1.959001687 5.460005926 AA598510 2 3D adult vs. fetal 2.698323673 2.653383075 1.709197068 1.448745687 1.852274765 5.166038663 AA453787 2 3D adult vs. fetal 2.702589425 1.620596967 1.717336506 1.499079329 1.522616002 4.378038549 H05655 2 3D adult vs. fetal 3.107515398 2.521892845 1.311805573 1.314199679 1.633779252 6.087070828 AA419177 18 3D adult vs. fetal 23.89742962 15.45485589 25.88217585 24.47790114 28.20825412 20.47309058 AA458807 18 3D adult vs. fetal 22.02916221 16.65443357 25.45874485 22.43485375 25.67182927 18.88009347 AA293218 18 3D adult vs. fetal 19.79668624 15.40443015 27.23128953 22.13209523 21.07504567 18.14351405 W44860 17 3D adult vs. fetal 12.7340951 10.689677 18.07307043 13.89427187 15.92917087 12.73205002 AA629862 17 3D adult vs. fetal 14.59679193 11.53376895 17.21229223 15.59989608 16.64541758 14.01615062 AA447674 2 3D adult vs. fetal 2.534264127 2.150154393 1.427789252 1.000328271 1.423442229 4.137781882 T52484 2 3D adult vs. fetal 3.236398407 3.026511181 1.838920999 1.617002106 1.759710423 4.94920807 AA496810 2 3D adult vs. fetal 2.803422463 1.595989735 1.728921373 1.455020012 1.72732132 4.877833042 AA486233 2 3D adult vs. fetal 1.105294528 3.612629566 2.016514163 1.407057353 1.146012765 4.325105426 AA079775 2 3D adult vs. fetal 3.60412957 2.70567137 3.009055265 2.126182568 2.517322618 5.903186938 W73889 2 3D adult vs. fetal 3.174704174 4.228312305 3.583500944 3.632704149 3.233152734 6.073296967 R50337 2 3D adult vs. fetal 2.252389181 1.301117771 1.696068083 1.246881305 1.59150746 3.84378734 R55046 2 3D adult vs. fetal 4.804068001 3.914420759 4.479334588 5.310431247 5.155223566 4.292901695 R46821 2 3D adult vs. fetal 4.481781503 3.60517107 3.194315863 3.736730328 4.059831528 3.62674894 R87763 2 3D adult vs. fetal 4.349371289 1.738958085 2.016576353 1.564246255 2.167157105 4.929744779 H89583 2 3D adult vs. fetal 3.472010108 3.168123065 3.070758833 1.876335035 2.529708287 5.529732134 R56040 2 3D adult vs. fetal 2.875034039 12.02198937 3.636042926 3.134295566 2.862500876 5.657443535 AA922705 2 3D adult vs. fetal 2.467900912 5.753848696 2.364224943 1.826235564 1.990935084 5.56199203 AA487571 2 3D adult vs. fetal 2.392095741 2.030046874 1.8982167 1.167380172 1.445241279 3.891969777 AA402440 2 3D adult vs. fetal 3.04018443 4.537574439 2.816667278 2.313436127 2.567871927 6.461198799 H29521 2 3D adult vs. fetal 3.458079561 2.089088468 1.722877258 1.456445529 1.929668192 5.361928045 AA490911 15 3D adult vs. fetal 42.67030392 26.52859985 36.28250422 40.39466602 41.60811969 34.97057694 AA486082 13 3D adult vs. fetal 10.41727609 8.937884327 15.05040142 10.82056372 11.95282018 8.842288293 AA678065 17 3D adult vs. fetal 14.12093138 11.54070062 20.86168208 18.075708 17.83849384 13.73636722 R43509 16 3D adult vs. fetal 11.02563598 9.509595949 16.74133733 14.13918278 13.48520494 10.63815358 N57653 16 3D adult vs. fetal 10.4123206 10.44346779 14.67805884 11.74181676 11.74500654 11.69858601 AA670955 16 3D adult vs. fetal 9.121610176 8.547640672 16.37945858 12.25345162 12.21640163 9.258251347 R14692 2 3D adult vs. fetal 0.757198559 0.588063899 0.752811699 0.852655502 1.447179728 0.869563322 AA488979 15 3D adult vs. fetal 33.66640515 23.40785359 36.22684956 35.83780071 36.1199539 29.2581877 AA443630 2 3D adult vs. fetal 3.179366912 1.141747364 1.766810452 1.118906727 1.631839103 4.49413229 AA027840 14 3D adult vs. fetal 30.77584038 23.58752538 32.62815407 33.05944103 33.60205655 25.63272733 AA458830 14 3D adult vs. fetal 25.58379208 26.39848683 28.15722788 25.87408416 27.40987838 24.06147297 AA459015 13 3D adult vs. fetal 10.03176884 8.709006371 16.03563015 13.10174715 14.03043114 9.884872553 AA074446 13 3D adult vs. fetal 11.85807943 9.620046415 13.82726113 12.87569434 14.04256345 11.73842466 AA027042 13 3D adult vs. fetal 12.73491005 9.459896144 16.51983878 13.49994947 14.93224524 12.43468402 AA629923 13 3D adult vs. fetal 11.09427639 6.096835847 11.63735402 10.20004947 10.48961254 9.430135362 AA460830 15 3D adult vs. fetal 43.46763026 25.89585549 36.23321738 37.95742356 39.87905887 37.77709716 AA454218 0 3D adult vs. fetal 4.470293684 3.093239424 4.937529756 4.688122666 5.072419486 3.72227458 AA046523 6 3D adult vs. fetal 6.155805263 4.388837355 6.934532229 5.949254753 6.883321967 5.158132106 R51346 0 3D adult vs. fetal 3.230511245 3.062418161 3.787520043 3.783285032 3.826003563 2.512202334 AA029964 0 3D adult vs. fetal 3.855847135 4.014123191 5.758888572 4.613362037 4.007280855 3.687657081 AA489219 0 3D adult vs. fetal 3.274998157 2.361717684 3.918052974 3.243068103 3.469099389 3.176498463 AA043133 0 3D adult vs. fetal 3.039842745 3.471121389 5.203529353 4.221352079 4.259092185 3.419382811 AA812973 17 3D adult vs. fetal 15.77248197 10.74549128 18.85394679 18.86663157 16.77333141 12.70379222 AA453471 0 3D adult vs. fetal 3.957168294 3.038926799 2.87937811 4.188692511 4.453834895 3.457945931 AA284693 17 3D adult vs. fetal 14.4127364 9.497839898 13.96717518 12.75585136 13.63554527 14.18625183 N90281 0 3D adult vs. fetal 2.889108898 3.065073021 3.825043424 3.772722446 3.897897917 2.916608408 AA629542 0 3D adult vs. fetal 3.339124505 3.20278143 4.020290022 4.367848138 4.203343071 3.045430554 AA679345 0 3D adult vs. fetal 4.041914565 3.40189177 5.334580535 4.767347184 5.052052168 3.629044952 H37774 2 3D adult vs. fetal 2.582136051 5.751409544 0.826130431 0.749198653 0.950396052 4.924705249 T97181 2 3D adult vs. fetal 2.848144946 1.762304259 1.780931817 1.662977237 1.930489483 4.429079742 AA454879 2 3D adult vs. fetal 2.588814818 1.895822968 0.788622997 0.683939522 0.868426864 4.58445785 AA147640 0 3D adult vs. fetal 3.111174182 3.689139309 3.781524296 4.096860799 3.959011774 2.732271995 AA767429 9 3D adult vs. fetal 7.054093591 5.363580152 7.988105567 6.839604508 7.370692262 7.981701609 AA490991 9 3D adult vs. fetal 10.98757317 7.790729538 12.35710247 9.885681916 11.00435577 8.898305631 AA422058 17 3D adult vs. fetal 14.71408525 14.84685565 24.49176062 19.94632048 19.29291385 14.68049409 N66208 9 3D adult vs. fetal 8.123797741 6.177962556 10.33188119 7.894725917 8.580898297 6.881934203 AA630776 9 3D adult vs. fetal 9.138119273 5.83233298 11.41953939 9.003209098 9.590093969 8.070647196 AA827287 9 3D adult vs. fetal 8.482649348 7.482270307 8.891746969 9.19984268 9.976725792 8.422494842 AA488084 9 3D adult vs. fetal 7.649134152 14.97955716 13.41766713 10.42093881 9.071703388 8.874743158 R89715 13 3D adult vs. fetal 9.750099751 17.8705502 18.03616416 13.82091334 12.99735343 14.90421282 AA490501 9 3D adult vs. fetal 7.944415444 7.85975819 11.06033198 9.284097489 8.992468434 7.63431741 N32199 9 3D adult vs. fetal 9.67828656 7.893329723 9.916311099 9.837236279 11.23987563 9.150031823 AA434404 9 3D adult vs. fetal 6.86730459 8.426674472 9.577263322 8.037236674 8.096867575 6.953180054 N93688 8 3D adult vs. fetal 5.038274076 10.94187624 9.036823839 7.358456237 7.155250657 6.336977302 AA292676 7 3D adult vs. fetal 11.09420423 9.867844396 9.548860422 11.52855409 12.53274971 9.824831453 AA464417 7 3D adult vs. fetal 10.40978662 9.6398749 11.95762629 12.77651551 12.8767479 10.07601153 AA442092 7 3D adult vs. fetal 9.965987122 7.370289148 8.883701613 9.441691799 9.667688043 8.214697052 AA442092 7 3D adult vs. fetal 9.965987122 7.370289148 8.883701613 9.441691799 9.667688043 8.214697052 AA026644 7 3D adult vs. fetal 7.769602383 6.638214592 5.137119018 3.572083072 4.086915401 15.10517784 AA481464 9 3D adult vs. fetal 7.356616049 9.394727631 11.96871523 9.624488789 9.697819022 7.196159079 T68859 12 3D adult vs. fetal 7.102239287 6.063011273 10.14342977 8.316121437 8.90719198 7.165656319 AA699560 13 3D adult vs. fetal 9.978421471 9.37295778 14.75863286 16.42689227 14.26471651 12.73562928 AA705069 13 3D adult vs. fetal 8.512749427 10.51595378 13.19983017 9.999000301 10.13397175 9.694546633 AA457739 13 3D adult vs. fetal 13.76296688 10.27635708 15.4062123 12.76652957 14.0993498 10.82804945 H99843 13 3D adult vs. fetal 11.42545366 9.860489604 11.08358091 10.09631162 9.902204667 10.73353077 AA399410 13 3D adult vs. fetal 11.49268913 9.868304848 16.50988414 14.49672712 13.23658995 10.91245055 AA443039 9 3D adult vs. fetal 8.661615681 5.473553572 10.7592073 8.268347579 9.771073691 7.541136242 AA164440 11 3D adult vs. fetal 17.82989233 11.87877628 20.35395821 18.48267711 19.46815644 14.70024382 AA446453 11 3D adult vs. fetal 16.55396138 13.81116994 16.50294651 19.54048563 21.22775124 16.02767268 AA280692 11 3D adult vs. fetal 17.40750225 16.18669704 19.04935817 19.71347085 20.1673057 16.35083848 AA031514 11 3D adult vs. fetal 20.58635757 17.50162009 21.03844179 22.39941193 21.41470955 18.33395551 R33154 11 3D adult vs. fetal 15.80929053 13.23696939 13.37191076 14.52813826 14.95312607 16.05415087 AA487452 11 3D adult vs. fetal 13.71327193 19.41866534 12.61831663 12.077349 12.74498437 18.11228999 AA400329 9 3D adult vs. fetal 9.471410325 8.139099224 9.945496246 10.13837609 11.074429 7.250594994 AA454668 13 3D adult vs. fetal 9.047350014 7.5254115 12.60652925 10.81932261 10.34313891 8.424799177 AA486393 23 3D adult vs. failure 0.682030067 6.724440565 0.800620868 0.562299276 0.603381368 1.639697615 R62541 23 3D adult vs. failure 0.402099116 2.047232943 0.476534818 0.419746076 0.364790601 0.848514165 AA171613 23 3D adult vs. failure 0.833916304 6.428013019 1.049489533 0.831618144 1.061543998 2.831110499 AA235706 0 3D adult vs. failure 103.2862145 45.18459033 36.30704958 66.22096461 76.19336098 53.68696068 AA668527 23 3D adult vs. failure 1.360133945 6.805032154 1.071215078 0.97529683 1.06310668 3.121521767 T64144 23 3D adult vs. failure 0.476915725 7.417782102 0.746262622 0.455935776 0.588907616 1.573719963 R14080 23 3D adult vs. failure 0.442812641 7.906110384 0.627950807 0.498614946 0.372466179 1.218619609 AA609599 23 3D adult vs. failure 0.359352461 7.143369152 0.569305177 0.366281857 0.341488403 1.345297086 AA489201 23 3D adult vs. failure 0.746247673 7.761267038 0.569230512 0.568039398 0.51445757 1.823393758 R08876 23 3D adult vs. failure 0.881300108 6.204438487 1.346594192 1.127374945 1.303511748 1.365140688 H46425 23 3D adult vs. failure 0.446119129 7.549550263 0.42423628 0.384125705 0.304256579 1.948954368 R56149 20 3D adult vs. failure 3.946739485 2.221889535 2.687396748 2.29349791 2.994436137 6.00466275 AA454619 20 3D adult vs. failure 4.670053967 2.36899368 3.285602699 2.811568095 3.530544823 6.168078813 H15445 20 3D adult vs. failure 3.638147066 2.706447087 1.458885277 1.457265129 2.021283714 6.315381377 AA705225 23 3D adult vs. failure 1.386836786 6.429576897 1.83711377 1.34483513 1.150500104 2.597429853 AA191488 2 3D adult vs. failure 2.174224052 45.10144344 2.069008838 1.631870516 1.77653582 16.32613468 N64862 14 3D adult vs. failure 0.650596095 12.10838017 1.065306504 0.665682947 0.614517248 3.167265877 R45413 7 3D adult vs. failure 0.716578413 26.61952355 1.065046051 0.917779985 0.773891766 6.012284228 R77293 7 3D adult vs. failure 4.173270014 18.87787869 6.098081459 6.158463331 5.192489399 6.808820493 AA436187 6 3D adult vs. failure 7.73084558 34.64438609 9.740301386 7.582520052 8.233604749 18.4559413 AA676470 5 3D adult vs. failure 23.09461759 12.79749882 19.67261192 18.83195374 25.31283192 19.5015243 AA443634 23 3D adult vs. failure 0.483674724 6.507766668 0.834546801 0.602237179 0.563061629 1.705323839 AA664180 4 3D adult vs. failure 77.28842805 43.66418943 36.30704958 68.26659959 73.01397471 54.50243711 W58658 20 3D adult vs. failure 3.738957043 1.157647486 1.625298607 0.567045634 1.362263758 5.290498458 H54023 2 3D adult vs. failure 2.518425666 76.64764128 1.455767277 1.89558391 2.244043815 23.68020326 H73724 11 3D adult vs. failure 0.794565272 15.90487626 1.124742532 0.660242857 0.688814595 4.296719254 T70031 2 3D adult vs. failure 2.006155548 48.92472369 2.789740103 2.01477414 1.746671803 15.29766287 AA481758 0 3D adult vs. failure 123.6211644 61.20693911 36.30704958 92.35920856 102.0498037 54.85301063 AA521431 0 3D adult vs. failure 125.2413904 56.77999766 36.30704958 93.6827224 100.8362156 54.85301063 AA446103 23 3D adult vs. failure 0.338624303 7.652704012 0.571045963 0.349989394 0.406883851 1.434663101 N92646 5 3D adult vs. failure 30.42865911 14.89709888 29.90172172 26.59339088 28.56672605 26.04183434 AA453789 18 3D adult vs. failure 2.044150452 8.495958017 2.328026154 2.572167528 2.212159729 3.457082607 AA425299 18 3D adult vs. failure 7.887770078 3.918963058 10.38387994 7.660089272 8.794304531 7.329938113 AA868929 18 3D adult vs. failure 1.98091121 9.937368538 2.013089465 1.471073914 1.420828724 5.418655459 R60019 18 3D adult vs. failure 2.116044289 8.525464296 1.047037018 0.928042539 1.082727505 5.235772895 AA857343 18 3D adult vs. failure 1.650037418 6.297808737 2.426871459 1.704623126 1.741966813 3.845429741 AA481438 18 3D adult vs. failure 2.573933498 8.391310909 2.445625176 1.893217317 1.76341218 6.043734557 AA399674 18 3D adult vs. failure 2.130783417 8.164685436 3.388970859 2.354039954 2.279993542 4.872785488 T98887 18 3D adult vs. failure 1.100740148 8.756420509 0.936100822 1.100317922 0.803584044 3.484794007 AA678404 18 3D adult vs. failure 1.601598727 7.015197466 1.932547665 1.820935977 1.80852363 3.313612045 H15747 20 3D adult vs. failure 3.703368787 1.841236561 1.31983711 0.468266355 1.579189807 6.384201738 H16958 16 3D adult vs. failure 4.911652574 2.505777016 6.153238607 3.258278988 9.421877751 2.976025283 AA936783 14 3D adult vs. failure 1.342031028 13.57092172 1.952974192 1.334954568 1.22240126 1.341547085 AA884709 18 3D adult vs. failure 2.262402026 7.467527538 3.158379807 2.652355075 2.663007264 4.51372877 H24688 18 3D adult vs. failure 1.395480263 7.059371875 2.232669864 1.921932565 1.963742023 4.014560107 AA884403 18 3D adult vs. failure 2.032526808 8.508216003 2.408869338 2.267218044 2.281983003 4.451591143 AA404619 19 3D adult vs. failure 0.721996555 11.04039228 0.849034927 0.475083665 0.645471218 2.92914746 AA598611 19 3D adult vs. failure 0.473381741 9.658226818 0.485642718 0.382776293 0.327497562 3.321739 H72875 19 3D adult vs. failure 1.047528607 9.965593016 1.7514717648 0.96145731 0.718146053 3.174877726 H63361 19 3D adult vs. failure 0.444705701 8.608586298 0.460617918 0.347764767 0.327526489 2.835780951 R39221 19 3D adult vs. failure 0.063457623 8.80369405 0.916404688 0.588441567 0.583832961 2.21717036 R02348 19 3D adult vs. failure 0.380957115 8.723284539 0.689843744 0.430680409 0.314907846 1.628641297 R51835 19 3D adult vs. failure 0.319821038 3.205091988 0.499133148 0.341800718 0.398772973 0.702868877 R33031 19 3D adult vs. failure 0.309199103 9.871901353 0.870719013 0.498982302 0.446815901 1.737947999 AA412053 18 3D adult vs. failure 2.173462159 8.658749377 1.560525939 2.335301865 1.60001113 3.312435004 AA001897 11 3D adult vs. failure 0.707399619 18.56199185 1.276833043 0.839394093 0.698445289 3.44857855 W81191 18 3D adult vs. failure 2.035130827 9.564497621 1.470028438 1.278460058 1.466681545 5.442558928 AA430552 16 3D adult vs. failure 6.704743363 3.912744879 7.308427625 6.182487835 6.715639324 5.892347254 AA594130 20 3D adult vs. failure 4.197684546 1.950948544 3.399747789 2.792799271 3.308148608 6.573561928 N92864 20 3D adult vs. failure 3.964889092 1.12030555 1.255047434 1.028875207 1.597688392 6.129597747 AA457123 20 3D adult vs. failure 3.825435082 1.372454684 1.737581719 1.805411888 2.242579776 5.776097858 R43320 19 3D adult vs. failure 0.534524185 10.13392358 0.307540341 0.334762409 0.297154033 3.300796986 AA670430 20 3D adult vs. failure 6.033965543 2.411089781 6.490413776 5.227507565 6.00488788 4.958892131 H85068 11 3D adult vs. failure 0.932240825 19.08305372 1.062851862 1.323524085 0.843208322 3.42676519 AA458785 11 3D adult vs. failure 1.024544481 14.76220711 1.673515465 1.016303139 1.117923958 3.660946499 AA485871 11 3D adult vs. failure 1.240425485 16.32124036 1.819664978 1.051475658 1.243832378 4.885742561 T39411 14 3D adult vs. failure 0.683416906 14.1280482 0.827762784 0.665895165 0.776309726 3.661139864 R00855 20 3D adult vs. failure 4.116868708 2.545089683 2.768201659 2.658761885 2.788015121 6.090967819 H98666 16 3D adult vs. failure 7.496261053 3.423039388 3.917399183 3.208047795 4.021338011 7.436138134 H72028 14 3D adult vs. failure 1.122387248 10.87725529 1.107269289 0.894651185 0.693097551 5.481280912 AA679177 14 3D adult vs. failure 0.813601986 11.3980019 0.884729818 0.738756843 0.624486657 3.353148409 N21578 14 3D adult vs. failure 0.493867961 12.22018711 0.630068988 0.332239214 0.452874405 3.48979683 AA007419 14 3D adult vs. failure 0.640548282 10.87290796 0.573707373 0.426598512 0.390973266 5.000691355 T49657 14 3D adult vs. failure 1.478438588 12.2454622 1.66172702 1.085853458 1.158150176 4.728340076 N38959 14 3D adult vs. failure 0.96668518 12.21521754 1.222240919 0.390241965 1.036587317 3.877992922 R51912 14 3D adult vs. failure 0.931685691 13.32666832 0.554065456 0.584470901 0.545379233 4.794685202 H90415 14 3D adult vs. failure 1.027933738 14.40938868 1.543560847 1.015015198 0.913466897 3.697172386 H41489 1 2D/3D adult vs. fetal 4.027389786 2.097422239 1.726349793 1.413362414 2.223616983 7.753646206 H16456 1 2D/3D adult vs. fetal 4.015386257 7.010456083 2.974647228 2.512493381 3.106940998 8.704678862 W45415 1 2D/3D adult vs. fetal 5.612363827 1.065216881 2.691703268 2.027056421 2.568973782 6.615995267 AA447751 1 2D/3D adult vs. fetal 3.707303465 4.780241073 2.223590687 2.437972778 2.631458156 7.623606101 AA487486 1 2D/3D adult vs. fetal 4.21336596 4.045765801 3.015283294 2.286202019 2.768948605 8.048478397 R56604 1 2D/3D adult vs. fetal 4.165186307 3.846779908 2.973815371 2.369929936 3.1509812 7.458099126 T65772 1 2D/3D adult vs. fetal 4.487863913 2.538286605 2.643015763 2.462140712 3.0062686448 0.741762884 H15085 1 2D/3D adult vs. fetal 4.532070688 2.552606255 1.874728576 1.797928653 2.249323538 7.10815384 R61295 1 2D/3D adult vs. fetal 5.7522625 3.64542013 2.945120833 2.564363772 2.826103944 7.68061273 T61256 1 2D/3D adult vs. fetal 5.260364 1.641968589 1.819566112 1.625856706 2.432049565 6.879367501 AA405731 0 2D/3D adult vs. fetal 2.090454022 34.42033666 1.664515998 1.304288382 1.293105338 10.6339838 T71879 1 2D/3D adult vs. fetal 4.193732889 4.210242665 1.985666897 1.946658119 2.195662508 8.143137484 R59927 1 2D/3D adult vs. fetal 4.826208077 4.383351971 1.602344146 1.52557434 2.192290627 7.925477266 AA496780 0 2D/3D adult vs. fetal 1.514704846 26.44459843 1.135159078 0.912692615 1.001084793 10.48006188 AA176888 0 2D/3D adult vs. fetal 0.883613375 16.90708911 0.969072645 0.759370466 0.781878516 6.758214974 AA436163 0 2D/3D adult vs. fetal 1.145286483 19.39007997 0.91032868 0.79908737 1.062812492 7.470804263 AA428778 0 2D/3D adult vs. fetal 2.705936237 23.81604244 1.650059764 1.291875843 1.526455491 10.05785097 AA463225 0 2D/3D adult vs. fetal 1.805467836 22.97689102 1.545226155 1.416083191 1.289595725 9.717200851 AA485426 0 2D/3D adult vs. fetal 1.389325695 25.67139954 1.27039293 1.069742478 0.998457685 9.858144828 W47485 0 2D/3D adult vs. fetal 1.745341956 27.39946025 1.287668441 1.305011386 1.416492719 11.04790889 H84982 0 2D/3D adult vs. fetal 1.533032723 28.30131199 1.047589817 1.549633971 1.23686481 9.828318446 AA504615 1 2D/3D adult vs. fetal 4.050257188 3.625356301 2.199703889 1.941384876 2.75118289 7.641495993 H94487 0 2D/3D adult vs. fetal 1.645750443 22.47903843 3.594820042 1.028845936 1.681686149 8.286429124 AA448959 0 2D/3D adult vs. fetal 3.124990125 4.592355812 3.899374735 3.173734392 3.451263958 6.793092921 AA070358 2 2D/3D adult vs. fetal 8.012667475 1.564102379 1.883538283 1.584996753 2.642393389 9.48000834 AA453401 1 2D/3D adult vs. fetal 5.692934592 1.528593629 1.905652383 1.904350696 2.206453207 6.672888766 N66737 14 2D/3D adult vs. fetal 24.90073908 0.393334078 1.095420779 0.556298638 0.923759381 3.442649218 AA666180 9 2D/3D adult vs. fetal 2.115740805 12.05725753 2.14570443 1.488045473 1.870792054 5.34373246 AA857131 9 2D/3D adult vs. fetal 0.152032673 0.207460704 0.268997471 0.210685319 0.132367162 0.357440795 AA479102 9 2D/3D adult vs. fetal 2.295197382 25.01632531 3.681214605 3.425928026 3.02851033 8.49611205 AA456077 7 2D/3D adult vs. fetal 7.731170292 4.509291885 4.761631135 3.922605205 4.875603995 11.60167555 R87497 7 2D/3D adult vs. fetal 7.553857203 4.518297667 3.006217917 1.067794468 4.393661357 12.60889243 AA718910 7 2D/3D adult vs. fetal 7.12414318 3.548431737 3.928552441 3.557814726 4.383101911 10.82120865 AA406269 7 2D/3D adult vs. fetal 5.887777587 6.493700059 3.376570613 2.359008775 3.447900579 11.90806873 N74623 4 2D/3D adult vs. fetal 0.738692411 0.885632206 0.507569185 0.423927496 0.405894222 1.326758097 H99364 6 2D/3D adult vs. fetal 4.654446832 3.967945222 3.173155342 2.53020258 2.826020625 9.199591084 AA447684 6 2D/3D adult vs. fetal 3.976408745 14.43816072 4.763738151 2.471882235 2.732135077 8.763139341 AA282301 6 2D/3D adult vs. fetal 5.741753046 2.638926534 3.525955597 3.116535142 3.442563042 8.08592064 H99588 5 2D/3D adult vs. fetal 1.455459706 29.42112357 0.93818073 0.705663294 0.91408074 9.587415089 N53512 5 2D/3D adult vs. fetal 1.885890833 27.43755749 1.437831064 1.488193294 1.489514434 11.66412529 AA683321 5 2D/3D adult vs. fetal 1.133236265 27.22345134 1.394968386 0.968365361 0.71972912 8.309498154 AA608557 5 2D/3D adult vs. fetal 2.577273943 29.04646478 2.807387159 2.029202014 1.932689792 8.478935818 AA757764 2 2D/3D adult vs. fetal 5.690914196 3.357895765 3.881101888 2.752079821 2.955536228 9.043391314 AA406064 2 2D/3D adult vs. fetal 6.957108219 3.855068049 3.928274978 3.830306615 5.143577569 9.248530935 N54598 20 2D/3D adult vs. fetal 6.411864475 40.45864114 12.32476105 8.740060641 8.361428458 11.67500348 AA481988 7 2D/3D adult vs. fetal 6.029716769 7.619281816 3.801345873 3.597022308 3.988124217 12.08244483 N62394 3 2D Marker adult vs. fetal 2.436813979 3.687865805 1.411911686 4.045770491 0.844150341 2.656973499 N20148 3 2D Marker adult vs. fetal 3.44995341 2.759942512 3.751806548 3.90090485 3.142378907 4.04494813 AA496678 3 2D Marker adult vs. fetal 7.001100843 4.03568563 5.297409583 3.722383923 5.160647823 10.19230959 AA400973 3 2D Marker adult vs. fetal 2.89346803 4.47076738 4.470210209 3.193478491 3.257043268 4.020015252 AA497027 3 2D Marker adult vs. fetal 1.802250483 0.578162102 3.922092662 2.407065102 1.286762868 2.157496735 N64508 3 2D Marker adult vs. fetal 2.115795984 3.276856168 1.90235047 5.314258483 2.788331395 3.540796101 AA033564 3 2D Marker adult vs. fetal 5.316788651 2.720044947 3.133883202 2.683871596 3.532284326 8.161295359 AA446108 3 2D Marker adult vs. fetal 2.078301935 2.211041944 3.792759943 3.324684095 3.375402585 2.756568814 AA159577 3 2D Marker adult vs. fetal 4.746090464 4.989070689 4.287813007 3.593768792 3.816425244 7.786959581 R36958 3 2D Marker adult vs. fetal 4.749539144 3.400588787 5.624793806 5.234422192 5.286395351 4.078616944 AA829508 3 2D Marker adult vs. fetal 1.920163507 0.7909906 3.923258324 3.457491381 1.13174848 1.710017559 AA482067 3 2D Marker adult vs. fetal 6.194625221 4.238881966 3.254611387 3.315340662 3.879401032 8.171254871 AA669314 3 2D Marker adult vs. fetal 6.809538669 4.133050912 5.329740351 3.780076886 4.424821889 8.385883026 AA775241 3 2D Marker adult vs. fetal 6.014247582 4.222679024 5.909433903 4.651935893 4.529769385 7.71821785 R73584 3 2D Marker adult vs. fetal 2.788220682 5.744755801 4.174172878 3.110031036 2.840523285 3.830886431 H28984 5 2D Marker adult vs. fetal 2.892697648 3.831327794 4.337837094 4.289702271 3.643114467 3.029043454 R44202 3 2D Marker adult vs. fetal 3.843410664 2.636358787 3.786734961 3.415590384 3.473443896 3.189323952 W70051 4 2D Marker adult vs. fetal 0.460743655 0.435637611 0.599111691 0.634647941 0.684508861 0.518398472 AA401972 5 2D Marker adult vs. fetal 4.694309329 5.237266898 4.803264368 6.3957827 6.187809857 5.273916388 AA236164 5 2D Marker adult vs. fetal 4.489190329 5.999132856 6.533218517 5.791985355 5.205993927 5.089326434 R22412 5 2D Marker adult vs. fetal 3.322360737 8.924589287 5.257612264 4.2528688 4.433039078 4.372991798 AA424804 5 2D Marker adult vs. fetal 6.72316462 4.945597359 8.844706058 7.100383442 7.690736998 5.712216735 AA669443 5 2D Marker adult vs. fetal 3.473141273 5.642074949 5.804136792 4.780513481 4.819190027 3.624913174 N69689 2 2D Marker adult vs. fetal 1.47268426 1.500609747 1.577772215 1.63158512 1.673578671 1.20775425 H24316 4 2D Marker adult vs. fetal 4.097759837 4.571809686 6.670594998 5.519559327 5.302346746 4.332423617 AA074224 3 2D Marker adult vs. fetal 2.916040437 42.17908573 3.996084321 3.421263628 2.977614141 15.7136877 R36571 4 2D Marker adult vs. fetal 1.22088245 0.697979245 1.246173941 1.106008283 1.434340053 1.173334441 AA058465 4 2D Marker adult vs. fetal 5.113683679 10.12779251 5.977620638 5.183053806 5.656909478 5.941479667 AA633811 4 2D Marker adult vs. fetal 5.047585747 3.541329987 5.859700035 4.917562173 6.033089317 4.6898963101 AA457155 4 2D Marker adult vs. fetal 4.59919155 2.634463051 5.207796008 3.444600254 3.888657977 4.888009989 AA459104 4 2D Marker adult vs. fetal 4.790849026 2.49717776 4.875933559 4.052637562 4.532277466 3.791654155 R40212 4 2D Marker adult vs. fetal 5.695606523 6.536605083 5.50014925 4.878309221 5.754823259 8.404118354 AA086476 4 2D Marker adult vs. fetal 3.826188364 2.338234619 4.05845178 3.573649092 3.942866534 3.486560771 AA683310 5 2D Marker adult vs. fetal 4.988875925 0.427535974 6.884450204 7.059542516 6.212911071 5.167664215 AA455640 1 2D Marker adult vs. fetal 2.29694825 2.246509212 2.490940902 2.65444359 2.528889751 2.024350751 AA496878 1 2D Marker adult vs. fetal 2.329206672 2.464809211 2.708923499 2.591526171 2.820757906 2.528269298 AA085749 1 2D Marker adult vs. fetal 1.134352576 1.145219423 0.919694908 1.213892433 1.191952306 1.148805945 AA425755 1 2D Marker adult vs. fetal 1.256026253 1.42629856 1.456101082 1.538376189 1.521167266 0.95599115 N52350 1 2D Marker adult vs. fetal 2.159542225 2.651354597 2.427419475 2.256040758 2.484151334 2.217863077 AA630104 1 2D Marker adult vs. fetal 1.898590687 1.850429013 2.323118997 2.265340283 2.543886171 1.567701571 AA454854 1 2D Marker adult vs. fetal 1.85505455 1.874219048 2.289079847 2.076882204 1.775527487 1.600396337 W73406 2 2D Marker adult vs. fetal 1.145861817 1.688694122 1.394720158 1.5150059 1.348266115 1.257230067 R12802 1 2D Marker adult vs. fetal 0.754036384 0.458756191 2.051238468 1.123879939 0.741672703 6.651716983 AA465355 2 2D Marker adult vs. fetal 2.427318967 1.234497382 1.382975298 2.820706627 1.758025333 2.561266549 AA829383 1 2D Marker adult vs. fetal 0.627874118 0.361600207 0.637447262 0.608221718 0.513908343 0.712979229 AA629189 1 2D Marker adult vs. fetal 3.384460323 3.907165525 3.933343191 4.23836901 3.468746044 3.982435808 AA430512 0 2D Marker adult vs. fetal 2.239479445 2.637756736 3.81876171 3.36943129 3.404540535 2.413395122 AA456439 0 2D Marker adult vs. fetal 3.838221727 2.779439139 4.396947289 4.325871481 4.445703612 3.414286314 H27864 0 2D Marker adult vs. fetal 4.083067399 2.588260193 3.247167731 3.682989494 4.052835461 3.076145132 AA644657 0 2D Marker adult vs. fetal 2.749565753 1.949529953 3.282718575 2.77240442 2.835386395 2.393138312 R40460 0 2D Marker adult vs. fetal 2.617741285 2.77044995 2.345768887 2.530348937 2.639132034 2.129569504 W96058 1 2D Marker adult vs. fetal 0.551793053 0.719935768 0.823172955 0.716948884 0.647054285 0.511406835 T72202 2 2D Marker adult vs. fetal 1.372133229 0.654777758 1.354496565 1.335828319 1.299148537 1.132910683 AA598794 3 2D Marker adult vs. fetal 0.857314271 0.38760124 4.80929041 4.449090919 3.2675415 0.950844105 AA599178 3 2D Marker adult vs. fetal 1.987500842 1.076238697 3.616532831 3.470498129 2.405945118 1.70047288 R88247 3 2D Marker adult vs. fetal 9.295559476 4.145659051 3.807036517 3.247695912 4.811556959 18.08933692 T98812 3 2D Marker adult vs. fetal 3.206007578 0.45582699 7.36008566 3.762388177 4.629393762 2.262352025 AA454858 3 2D Marker adult vs. fetal 7.687530164 3.130374276 3.770230181 3.357268094 3.90840295 11.3903899 N67048 2 2D Marker adult vs. fetal 0.182901012 0.36769394 0.297974786 0.30807128 0.27564065 0.333601513 AA776875 2 2D Marker adult vs. fetal 1.088783309 0.850650279 1.034076531 1.167561655 0.998364163 0.903409454 H51117 2 2D Marker adult vs. fetal 0.537932542 0.687368102 0.574022043 0.730299571 0.683526033 0.743361636 N36174 5 2D Marker adult vs. fetal 6.089061165 4.481415857 5.540191589 5.623320599 6.588429457 4.496005766 AA777187 2 2D Marker adult vs. fetal 1.523155704 1.077976801 2.060524963 1.946327352 2.299471554 1.87592009 R09581 8 2D Marker adult vs. fetal 5.890519553 3.784033955 5.786261707 4.733579692 4.524489662 5.169772778 R16849 2 2D Marker adult vs. fetal 1.23979305 1.31739538 1.989966506 0.663751034 1.594500153 1.415959831 AA884167 2 2D Marker adult vs. fetal 1.217420137 0.76877689 0.848143007 1.070264972 1.102669725 1.097445419 AA136983 2 2D Marker adult vs. fetal 1.988298813 2.638681789 2.540675832 2.650969074 2.517626988 1.836297875 AA488622 2 2D Marker adult vs. fetal 1.834368714 2.664699416 2.916200392 2.716178444 2.280636291 1.670136989 AA699427 2 2D Marker adult vs. fetal 1.74393914 2.642651634 2.705734803 2.790851259 2.361629453 1.978094745 AA490459 3 2D Marker adult vs. fetal 6.36833046 5.671979456 3.680374244 4.936768605 4.884731709 9.255585154 AA626787 2 2D Marker adult vs. fetal 1.688259404 2.164212705 2.115946285 1.795197631 2.352850319 2.121107168 N62179 15 2D Marker adult vs. fetal 35.50826346 19.11160591 33.5269723 27.57938931 35.32468308 29.21398971 N27190 16 2D Marker adult vs. fetal 9.750993225 7.530891576 12.75918957 11.05916225 12.03535219 8.653835849 AA441895 16 2D Marker adult vs. fetal 7.177282564 5.235719613 7.385439482 7.014086953 8.126515643 6.246092446 AA463924 16 2D Marker adult vs. fetal 10.41970608 7.964616858 12.55072628 11.42665371 12.31290239 9.520621452 N78843 16 2D Marker adult vs. fetal 7.66464154 5.43569693 7.61347718 7.608367958 8.883600715 5.827918931 AA629719 16 2D Marker adult vs. fetal 14.07113881 8.07158282 15.07029688 13.18842124 13.89479922 12.78716552 AA404755 16 2D Marker adult vs. fetal 10.9079267 19.01587747 12.27393806 10.03671065 11.20438161 12.29601389 AA459351 7 2D Marker adult vs. fetal 3.30738816 5.313693876 7.122668851 3.529883953 3.671031365 4.776266565 AA488346 16 2D Marker adult vs. fetal 9.488691926 7.542950447 11.21693205 9.805337766 10.46454533 9.180810589 AA427899 17 2D Marker adult vs. fetal 13.3365169 9.041851128 16.97946166 12.44206045 15.16820039 11.53880939 AA453813 15 2D Marker adult vs. fetal 23.53014662 18.55051373 26.13232552 24.07754444 27.05702114 19.41686645 AA397824 15 2D Marker adult vs. fetal 28.08351962 20.62648968 27.02787266 26.29257303 30.85067131 19.80045327 AA633901 15 2D Marker adult vs. fetal 34.77984918 23.78442887 36.12250762 35.61488434 41.66703684 30.60345109 AA181334 15 2D Marker adult vs. fetal 27.28075277 18.98160489 31.18437988 27.23129085 29.89868199 24.05531978 AA292410 15 2D Marker adult vs. fetal 31.30959843 29.13821092 33.60796008 35.98378599 38.0810897 27.93817331 AA253434 15 2D Marker adult vs. fetal 27.28836746 24.48751872 26.021072 29.51377393 31.81897761 24.38068282 AA455058 16 2D Marker adult vs. fetal 12.54762444 10.90299499 12.04192978 13.96133558 14.93518352 10.87358414 R55188 21 2D Marker adult vs. fetal 31.12874965 12.81904882 26.29604395 18.72935308 27.16189634 19.64403686 AA465723 0 2D Marker adult vs. fetal 0.626099905 0.519829853 0.965056345 0.801834491 0.723063592 0.645073541 N49856 23 2D Marker adult vs. fetal 58.25496123 43.81206927 36.30704958 58.88107815 63.73545411 51.53609212 AA455272 23 2D Marker adult vs. fetal 78.7226545 57.95745288 36.30704958 70.83386123 84.60136833 54.29877782 AA459292 23 2D Marker adult vs. fetal 84.98013907 54.55237528 38.30704958 78.81031291 85.94545998 54.78113735 AA878561 23 2D Marker adult vs. fetal 91.89023489 70.24733836 36.30704958 85.95771786 103.4556246 54.83812392 AA772068 23 2D Marker adult vs. fetal 100.7022767 60.91386332 36.30704958 95.8034517 85.63154687 54.85301063 N78821 17 2D Marker adult vs. fetal 18.18260113 8.900969331 17.95968118 14.88223883 16.81550288 14.041252 AA291490 21 2D Marker adult vs. fetal 16.15200019 12.2589771 19.64085664 16.98965403 18.88134711 13.99432924 N46828 17 2D Marker adult vs. fetal 16.54096886 9.830784212 17.53351276 13.86763897 16.838674726 15.02548971 AA150487 21 2D Marker adult vs. fetal 15.19512412 13.80042191 17.95609277 14.5094675 17.55056275 15.10253571 AA282537 21 2D Marker adult vs. fetal 17.24244099 13.64870386 21.82923027 18.53902602 18.34433042 17.95537212 AA707922 21 2D Marker adult vs. fetal 29.52423481 19.17248102 30.42814242 29.09439668 27.854176 25.96068749 AA443638 20 2D Marker adult vs. fetal 15.1000594 15.15348782 17.88558853 15.7697112 18.94151907 14.61633105 W73892 19 2D Marker adult vs. fetal 53.62002013 39.02380655 36.30704958 56.67674826 53.82921611 46.25990911 N70734 19 2D Marker adult vs. fetal 50.1395528 37.01986341 36.30704958 48.48335304 47.57551429 45.25023946 H57136 13 2D Marker adult vs. fetal 10.27199646 9.124487788 12.5238108 9.80585148 11.12532179 10.90999216 AA700414 29 2D Marker adult vs. fetal 72.81271834 37.61546462 36.30704958 68.67343991 62.25292659 54.4411949 W65461 7 2D Marker adult vs. fetal 5.476839239 5.067442981 5.426887725 6.079126118 6.4014634348 5.626362584 AAA36584 15 2D Marker adult vs. fetal 23.02941313 15.24754038 25.73740515 22.61556954 22.7981159 19.91483801 AA029042 9 2D Marker adult vs. fetal 8.022234644 7.311596005 8.895662277 9.479217739 9.605485934 7.544837461 AA427725 9 2D Marker adult vs. fetal 12.69294864 7.655536142 13.67326812 4.261155334 12.4290971 12.81248352 N51280 9 2D Marker adult vs. fetal 6.632333815 5.874595041 7.385166272 7.520608106 7.785748506 5.963530521 AA281347 8 2D Marker adult vs. fetal 5.089780613 4.640487592 4.9415594344 5.45251025 6.288204512 4.490066004 AA402960 8 2D Marker adult vs. fetal 4.965150621 4.50182924 6.596223821 2.242032928 4.880356598 4.839655851 N98485 9 2D Marker adult vs. fetal 7.125405927 6.544129951 7.7721864 7.556753899 8.479066808 6.411666818 AA490209 7 2D Marker adult vs. fetal 5.803194729 5.024903 4.546705412 6.046321655 6.500609214 4.920009122 W61361 9 2D Marker adult vs. fetal 7.384750912 7.335298925 11.10935518 8.8100027 9.421761776 6.881790584 N51018 7 2D Marker adult vs. fetal 5.488100802 38.59262312 10.6998308 6.032584586 5.216849242 17.32422488 AA455281 7 2D Marker adult vs. fetal 6.998082782 9.317433876 8.495460011 7.352959068 7.938571107 8.110370507 W69471 7 2D Marker adult vs. fetal 7.215022797 8.148565459 8.197656911 5.32000885 4.956859017 13.55485747 AA486321 7 2D Marker adult vs. fetal 6.616843406 3.688421667 10.1148224 5.538922361 5.404776773 6.062776617 AA458982 7 2D Marker adult vs. fetal 6.961286958 6.280975266 6.441469774 7.072922475 7.646598009 6.402438243 AA442095 7 2D Marker adult vs. fetal 10.53368867 6.969251828 9.035104314 8.530732052 8.715924875 7.353607298 N99003 7 2D Marker adult vs. fetal 7.777346527 5.123406597 7.271360835 7.694076299 8.015056524 6.947984869 AA609284 7 2D Marker adult vs. fetal 5.203527631 6.725228727 5.962252816 5.392872692 5.486984016 6.647332466 AA195036 12 2D Marker adult vs. fetal 4.739031812 5.630223489 6.168419327 3.952137125 6.299183956 4.511434885 AA478268 5 2D Marker adult vs. fetal 4.587623085 4.319668521 6.07446736 5.321094819 5.705783899 4.273131909 AA608583 13 2D Marker adult vs. fetal 8.710213419 6.633631914 10.89267006 9.897803204 10.76405611 7.594364628 AA480435 13 2D Marker adult vs. fetal 10.66603107 6.878393398 11.70702321 9.862860466 10.62920807 10.9035389 AA505046 13 2D Marker adult vs. fetal 6.175908969 7.774740452 10.84632581 7.657584613 7.632328468 5.432221512 AA487893 13 2D Marker adult vs. fetal 6.28913391 7.086629819 10.38317033 8.186637919 8.677781639 6.646527414 AA292226 12 2D Marker adult vs. fetal 6.978311765 9.498379167 9.999757753 8.245173408 8.45533271 7.944255354 H87106 9 2D Marker adult vs. fetal 8.511773166 8.306766068 8.639728411 8.688270747 9.817268292 7.409517924 W96450 12 2D Marker adult vs. fetal 6.333304604 6.11454874 10.93854816 8.295025536 8.501848685 6.781838425 N33331 13 2D Marker adult vs. fetal 12.01197758 9.753283045 14.0583162 10.92456794 13.45540044 19.89513482 AA405800 12 2D Marker adult vs. fetal 6.121396479 5.223320588 7.721500548 7.718106658 6.462547598 5.753462094 T51539 12 2D Marker adult vs. fetal 6.489900146 6.570558251 9.469029997 8.820264288 9.194419114 5.883142749 N59764 12 2D Marker adult vs. fetal 7.600540659 4.756724822 8.39191538 7.279906425 8.135204655 6.251234677 AA521346 11 2D Marker adult vs. fetal 18.0187463 11.98813991 20.04539147 17.66437285 19.72793582 15.44668566 AA428551 11 2D Marker adult vs. fetal 11.81379838 9.132344514 13.57703545 12.536771 14.26115078 11.3197892 AA489383 11 2D Marker adult vs. fetal 10.07196453 6.40710185 10.63654538 9.115267349 9.345806882 8.56845107 AA490172 11 2D Marker adult vs. fetal 8.374766147 1.415297485 17.38713256 12.09049918 8.290346893 6.184780432 AA504477 12 2D Marker adult vs. fetal 5.417891216 3.85972235 6.090353431 5.209247321 5.829042051 4.969815506 Accesion H1 V2 t0 H1 V2 t2d H1 V2 t4d H2 P1 3D H2 P1 2D H3 F P4 t0d H3 F P4 t2d H3 F P4 t7d AA283693 3.60E−02 7.00E−02 0.322383183 0.447391374 0.257739798 0.143513725 0.213829818 5.224212686 AA845156 1.28342518 1.863140939 1.384248489 1.041642418 1.859400083 1.332668422 1.018759388 5.129921131 R52548 24.22599845 23.2864338 18.34158303 25.57074708 22.01795031 27.50011776 26.82422658 0.455256887 T67128 0.104460037 3.43E−02 1.158151225 0.122945522 0.194757907 0.263409159 0.266372201 15.92056233 AA845015 5.971265034 6.563146942 3.845471328 4.218022136 6.266907187 4.459497525 3.113814791 23.77610407 AA937895 0.452860231 0.364695951 1.498136505 1.34894881 1.524476699 1.004544129 0.332861119 23.03713043 AA844998 11.26686885 9.619376872 4.163473688 8.673344954 10.804701 11.6741356 8.48774821 0.687222458 AA844518 48.83476799 54.52879325 40.56584843 54.89200718 49.39056409 42.93573187 47.44855774 6.960856259 AA894557 49.93664852 44.42230199 49.4951755 65.92881949 60.33602671 39.11417155 46.47247102 1.451948868 AA872001 54.20005466 64.75076884 65.42329615 62.45668946 67.24659793 53.73423923 63.31563058 1.313345062 H09590 0.653737608 0.390597399 1.521400852 0.559410558 0.287251416 0.132045049 5.76E−02 9.888630279 AA888278 4.209025695 6.432026011 1.564621676 2.03670347 3.658833325 5.897415558 5.585056007 4.869119818 AA490855 7.139496238 7.480509788 2.402406359 2.11287386 3.291155604 4.163992221 4.626992228 4.040992653 H05820 0.250153138 0.2218924 0.884601448 0.443767203 0.853117504 0.577197042 0.227069034 8.569006814 N57766 0.161049809 1.029762957 0.860155011 1.160409378 0.696379763 1.945055757 1.505490705 18.21699443 AA873885 0.576137629 0.747123686 1.364947624 0.484042151 0.351548888 2.300286033 1.86211811 31.75585388 AA878880 0.214554665 0.751859199 1.555155015 0.580037834 0.413262131 0.487069801 0.493477276 17.65353573 R54818 0.646985459 0.409947934 0.199952191 0.325728665 0.57824012 0.478785614 0.148018732 5.693624857 AA458830 10.09192142 11.58519602 4.33841323 6.048695063 5.824480196 13.79679438 10.66742276 10.18586889 W37884 2.917746898 4.089689479 1.262910319 1.511275797 1.980865808 5.197874299 6.453757844 5.811360752 N63192 3.165162737 4.106218227 1.558423149 1.5903832 2.110133253 5.489587577 6.303860434 5.163746261 R55789 5.839714648 7.877144785 2.228165523 3.701220707 3.164509514 3.916307321 3.178401276 3.905915697 R56871 8.541201281 9.565561925 5.095438247 5.327868943 7.13865299 8.798222752 9.999533942 1.720941975 AA448659 6.40985601 8.062945347 2.837008591 2.740282482 3.524896196 8.26644815 9.131700385 6.724601997 AA235388 5.495213871 7.128779744 1.810297945 3.365604514 4.797167927 5.188848193 3.719920825 3.55603538 W37769 7.944164954 9.806778833 2.976028459 4.717147657 6.792587093 10.44168598 10.83208914 8.961263558 AA421701 8.998110252 11.20923244 3.344552795 4.634853853 5.630305124 9.009982779 7.214242967 8.676253864 NB1029 12.53804212 11.46996906 3.601513562 9.079241362 7.051304119 8.667406893 7.19394857 6.694763747 AA644128 11.11148757 10.68939675 3.391349693 5.57092524 5.21033759 8.326957952 9.801034583 8.395745244 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0.397440561 0.456001183 0.419248288 AA633768 0.760761379 0.497766033 5.606806863 0.633870185 0.393352577 0.351794529 0.601192682 1.14487198 AA496880 0.493894518 0.572564726 6.056796145 0.653312475 0.514470842 0.502539979 0.501308175 1.212402498 AA625632 0.842550697 0.850281232 10.68487135 1.661720166 0.695569959 0.498447008 0.274386994 1.69499 R40850 0.394670064 0.363742341 4.967702878 1.362523305 0.380406218 0.141276114 0.169003657 0.619590829 AA486072 1.063850678 3.668838298 12.43527006 3.538640747 0.712197565 1.714315274 1.299858757 2.072066795 N80129 0.10312387 0.42006458 10.27394074 0.364964803 0.173871475 3.53E−02 9.69E−02 1.445787697 T67270 0.706906482 1.1288523 9.031533244 1.747487433 1.676363321 0.971529338 1.02792629 1.159935914 AA776304 1.05308668 1.608943664 7.115065643 1.060601139 1.428674622 1.215371395 1.026193827 2.050698416 AA64743 0.720584255 1.207641114 6.709648148 1.123344154 0.916034946 0.548390406 0.6724641 1.948529432 AA663983 2.040575612 0.913188385 5.16313531 1.007867654 1.323649464 2.135989003 8.32E−02 3.811870062 AA634008 1.359339921 1.036497507 13.34177496 1.724576212 0.853238694 1.024786523 1.068524094 1.956193928 AA683050 1.013489887 1.038528355 15.81952721 1.58843476 0.496740614 0.558453728 0.815020862 1.866191062 AA775874 0.246852476 0.424685862 5.143824512 0.974500161 0.529437509 0.290250898 0.38554521 1.21495112 AA029934 10.39261667 6.173829216 3.256015168 2.937213126 3.76308931 6.716135076 4.994432581 4.353783816 AA872397 46.00745138 39.17088563 36.04470776 60.24320179 47.48372041 40.84667624 48.51971658 25.61671577 AA428195 5.50376757 5.85445104 2.298660486 2.154530299 3.416182085 4.515305124 4.564251077 3.09255509 AA478724 2.441015531 4.011719078 1.703691212 1.339633614 2.575865932 1.573760187 1.247433101 2.275822402 T40541 0.275153908 0.545092967 3.902618974 0.963575617 9.51E−02 8.50E−02 3.92E−02 1.06319634 N33214 0.13076449 0.257442727 1.248745094 1.214456176 0.147732522 0.479395409 5.23E−02 1.778833698 W69399 0.345223646 0.364082141 1.11200994 0.651631382 0.156264888 4.35E−02 5.26E−02 1.090858575 H85454 0.177423187 0.164239157 0.25952362 0.278813589 0.207718277 0.192428939 0.293284362 0.980664216 T71284 3.25E−02 4.43E−02 4.34E−03 0.114965169 0.174872171 0.141660059 0.315197363 0.637643567 N95418 7.17E−02 4.56E−02 0.17695605 0.230927882 2.96E−02 3.19E−02 1.92E−02 0.409050075 AA430675 29.3586379 28.49610318 30.86231132 32.28482203 44.49536923 33.27001036 32.81546787 20.72524354 AA682851 46.90243645 42.6704861 49.46272263 54.93185512 60.11034283 37.00532862 37.62408166 23.34221611 AA427433 4.590770914 6.491096293 2.119161449 2.512849593 3.622778825 5.405043355 5.599238453 5.427644127 AA100296 39.44423876 56.23942898 41.49374024 50.80500421 43.55754452 57.54473062 53.89058071 27.20955224 AA070997 44.50541019 42.47813824 34.76574485 44.39487164 50.26187697 33.36357052 29.205598 27.82261502 R27585 35.33261308 33.39411146 29.7220802 41.54702124 41.6509187 34.23348926 26.42844313 25.01170127 N71628 29.62587768 25.73280775 27.314568 42.44280692 32.44686223 28.50781759 31.40872062 17.11695396 AA484566 36.70082765 34.8718366 38.3684724 32.25023119 37.7985424 98.44938631 22.42777135 AA043228 35.07501988 35.26683595 39.99311042 38.42578454 28.64861089 33.09819082 42.01213318 20.20000016 AA478273 24.39470164 24.77474479 23.18365645 21.88455412 23.61056895 34.11709903 37.1720164 22.29749728 H05618 0.287634172 0.126355776 0.103328665 0.53496355 0.113769783 0.103142991 0.103572238 0.411960124 AA405562 13.78665714 15.04195781 4.06566807 10.07318456 10.12150087 9.869201884 10.11315283 9.063379829 AA147043 10.06577793 10.38848924 8.480460276 9.593900583 10.3223246 9.358593384 9.251590954 7.969342929 AA035384 12.04070004 12.92252006 15.89036927 11.03937435 13.98924616 10.56026075 7.850369977 8.464122084 R60150 9.633059103 11.34413022 3.55905762 5.14548369 8.554543073 8.219606806 10.11952936 7.877309364 N64051 20.20297 17.93454359 6.059875542 10.65425592 11.69250488 14.02690246 13.40703529 11.39979162 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29.92364688 26.88595169 28.03401198 23.03958218 AA405800 25.43365191 26.8056176 19.34783059 23.9119729 29.14739213 20.1376127 20.7481208 15.45920589 T51539 37.04254749 35.58329862 27.22357679 29.39443068 29.26747712 32.85179948 37.13241221 24.37523886 N59764 24.30305591 21.24727999 22.53923803 16.07436069 26.90427658 20.92597239 23.22437469 16.44600319 AA521346 3.927462453 4.483573541 4.871009817 5.009623854 4.220279816 6.412726238 6.63139433 4.36497316 AA428551 7.511216326 7.054388812 6.360096869 6.367864337 4.74719124 11.79753397 11.90853014 8.624379722 AA489383 3.254207402 4.363727468 3.602198976 2.857452654 3.681140068 6.505644423 5.294661541 0.416874791 AA490172 8.563846144 2.818134846 16.5090439 6.336351989 4.552424226 5.084900046 1.540288648 5.753606895 AA504477 20.27058266 23.61171293 22.8431745 20.63453263 28.05090535 20.61037432 19.19136064 15.10292793 

1-29. (canceled)
 30. A method for the identification of tissue/cell specific marker genes comprising a) taking tissue and/or cells of at least one developmental stage and/or at least one disease state, and/or cultivating said tissue and/or cells in vitro under at least one culture condition, b) determination of gene expression profiles of said tissue/cells and/or in vitro cultivated tissue/cells and c) identification of specific marker genes by bioinformatic analysis of said gene expression profiles.
 31. The method of claim 30, comprising cultivating tissue/cells of at least two different developmental stages and/or disease states in vitro under at least two different culture conditions, determination of gene expression profiles of said in vitro cultivated tissue/cells and identification of specific marker genes by bioinformatic analysis of said gene expression profiles.
 32. The method of claim 30, wherein said tissue/cells are selected from the group consisting of fetal tissue, adolescent tissue, adult tissue, healthy tissue and pathological tissue, progenitor cells like stem cells or cells derived from the same precursor lineage.
 33. The method of claim 30, wherein said culture conditions are 2D and 3D in vitro cultures.
 34. The method of claim 30, wherein said gene expression profiles are determined by a micro-array.
 35. The method of claim 30, wherein said bioinformatic analysis is done by software analysis like e.g. SOM or cluster analysis.
 36. The method of claim 30, where the tissue is cartilage.
 37. A method for the quality control of tissue biopsies and/or cells/tissue cultivated/produced in vitro comprising the steps of establishing a gene expression profile of said cells or tissue, comparison of said resulting profile with profiles characteristic for a particular status or physiological potential of the examined cells/tissue and determination of the particular status of the examined tissue/cells.
 38. The method of claim 37, wherein said profile is a gene expression profile which is determined by means of a micro-array.
 39. The method of claim 37, wherein said tissue is cartilage tissue or chondrocytes, preferably derived from arthritic joint tissue (rheumatoid and osteoarthritis), and a micro-array comprises polynucleotide probes of tissue specific marker genes.
 40. The method of claim 37, for the assessment whether the tissue biopsy/cell samples can be used for culturing cells in vitro, the cultured tissue/cells being suitable for and/or used in the treatment of cartilage defects.
 41. The method of claim 37, for the assessment whether certain therapeutic approaches such as tissue engineering therapy, cell therapy or surgical therapy can be performed.
 42. The method of claim 37, for the evaluation of the quality of an in vitro produced implant or of in vitro cultivated cells for cell therapy.
 43. The method of claim 37, for the use in diagnosis within clinical applications and gene expression profiles used as a diagnostic tool therein, said method comprising assessing patient biopsy/cell samples for functionality, culturing functional cells in an in vitro cell culture to get cultured cells/tissue for the treatment/performance in a cell or tissue based therapy.
 44. The method of claim 37, for the use in diagnosis within clinical applications and gene expression profiles used as a diagnostic tool therein, said method comprising assessing patient biopsy/cell samples and deciding on a subsequent therapeutic approach, said approach preferably being selected from the group consisting of tissue engineered therapy, cell therapy, and traditional surgical approach.
 45. The method of claim 37, for the use in quality control and gene expression profiles used as a quality control tool therein, said method comprising assessing the quality of human biopsy/cell samples prior to performing a cellular expansion in case of cell therapy and/or prior to performing the differentiation/tissue formation in case of a tissue engineering therapy.
 46. The method of claim 37, for the use in quality control and gene expression profiles used as a quality control tool therein, said method comprising assessing the quality of the final implant prior and/or after product release, said implant being proliferated cells in case of a cell therapy or tissue engineered cartilage in case of a tissue engineered therapeutic approach.
 47. A method for the determination of characteristic gene expression profiles for clinical use comprising: a) determining gene expression profiles of tissue or cell samples in vitro and generating a database containing said gene expression profiles, b) correlating patient datas e.g. patient history, medication etc. of the tissue or cell sample donor with the gene expression profile of said tissue or cell samples and optionally the clinical outcome after treatment.
 48. The method of claim 47, wherein said gene expression profile has been determined by a method for the quality control of tissue biopsies and/or cells/tissue cultivated/produced in vitro comprising the steps of: establishing a gene expression profile of said cells or tissue, comparison of said resulting profile with profiles characteristic for a particular status or physiological potential of the examined cells/tissue and determination of the particular status of the examined tissue/cells.
 49. A cartilage array comprising a plurality of different polynucleotide probe spots stably associated with a solid surface of a carrier, whereby each of said spots is made of a unique polynucleotide that corresponds to one specific cartilage marker gene.
 50. The cartilage array of claim 49, comprising at least two spots that have different nucleotide sequences but of the same cartilage marker gene.
 51. The cartilage array of claim 49, comprising at least 10 spots of different nucleotide sequences and being indicative of a specific tissue or cell status.
 52. The cartilage array of claim 49, comprising spots of different nucleotide sequences and that are indicative for at least two tissue or cell status, preferably 3 status.
 53. The cartilage array of claim 49, wherein at least part of the cartilage marker genes is selected from the 467 genes listed in the description, preferably at least 10%, more preferably at least 50%, most preferably about 100%.
 54. The cartilage array of claim 49, wherein said different polynucleotides of the array do not cross hybridise under stringent conditions with each other.
 55. The cartilage array of claim 49, wherein the status is selected from biopsies and/or 2D cultures and/or 3D cultures of healthy adult, healthy fetal/infant, undesired adult, undesired fetal/infant or progenitor cells like e.g. stem cell or cells derived from the same precursor lineage.
 56. The cartilage array of claim 49, wherein the polynucleotide probes have a length of at least 10 nucleotides, preferably at least 25 nucleotides.
 57. The cartilage array of claim 49, wherein the carrier is optionally attached to coated glass, nylon or any other material.
 58. The cartilage array of claim 49, wherein at least part of the cartilage marker genes are selected from a subgroup of the 467 genes listed in the description, said subgroup consisting of the most tissue specific 200 genes.
 59. The cartilage array of claim 49, which can be used within clinical applications as a diagnostic tool in order to assess patient biopsy/cell samples for targeted in vitro cell culture treatment/performance when performing a cell or tissue based therapy.
 60. The cartilage array of claim 49, which can be used within clinical applications as a diagnostic tool in order to asses patient biopsy/cell samples and to decide on subsequent therapeutic approach which maybe a tissue engineered therapy, a cell therapy only, or even a traditional surgical approach only.
 61. The cartilage array of claim 49, which can be used as a quality control tool in order to assess the quality of human biopsy/cell samples prior performing the cellular expansion in case of cell therapy and/or prior performing the differentiation/tissue formation in case of a tissue engineered therapy.
 62. The cartilage array of claim 49, which can be used as a quality control tool in order to assess the quality of the final implant prior and/or after product release, said implant being proliferated cells in case of a cell therapy or tissue engineered cartilage in case of a tissue engineered therapeutic approach.
 63. A kit for use in a hybridization assay comprising a cartilage array of claim
 49. 64. The kit of claim 63, wherein said kit further comprises reagents for generating a labeled target polynucleotide sample, a hybridization buffer and a wash medium.
 65. Use of a cartilage array of claim 49, for in vitro diagnostic of mammals, in particular humans.
 66. Use of a kit of claim 63, for in vitro diagnostic of mammals, in particular humans. 